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A Closer Look At Lecanemab Donanemab And Amyloid · Dementia Researcher Vodcast

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- [Voice Over] The Dementia Researcher Podcast,
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talking careers, research, conference highlights,
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and so much more.
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- Hello and welcome to another episode
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of the Dementia Researcher Podcast.
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I'm your host, Dr. Anna Volkmer,
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an NIHR funded senior research fellow at UCL
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and a speech and language therapist.
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And I am absolutely thrilled
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to have you join us for today's session,
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which we've titled lecanemab, donanemab and amyloid.
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Although this is such a fast moving area,
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I am sure there will be two more emabs
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by the time we finish.
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Now, this topic was identified by our very own listeners
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as something they wanted to hear about.
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And it isn't just our listeners, aducanumab,
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lecanemab, amyloid or donanemab, lecanemab,
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they're such a mouthful and amyloid
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have made it to the mainstream media.
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And the current trials are a popular topic of discussion
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amongst patients and family members
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whom I work with in my clinical role.
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Well, today's guests are here to tell us all about it.
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They are three extremely experienced researchers
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who have made massive contributions to this field,
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two of whom I have the absolute pleasure
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and privilege of working with clinically.
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They are going to explain the facts
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and dispel some of the myths.
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So by the end of today's podcast,
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we will have a much clearer understanding
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of the amazing work going on in this area of research
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and the future challenges in this field future.
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So let's meet our guests.
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(logo chiming)
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Now it's my pleasure to introduce Dr. Cath Mummery.
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Professor Sir John Hardy and Professor Nick Fox.
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Hello everybody.
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- Hi Anna.
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- Hi.
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- Hi, Anna.
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- Hi, Nick.
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Why don't you tell us all a little bit about yourselves.
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So, Dr. Mummery, can you go first?
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- Sure. And that was a really kind introduction, Anna.
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Thank you. Far too kind.
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So I'm Cath Mummery.
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I'm a neurologist
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and I work at the Dementia Research Centre alongside Nick.
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He's literally next door in the next office.
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I am clinical lead for the service.
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So planning what we are gonna be doing
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with these therapies in the future, hopefully,
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but also have been doing clinical trials,
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looking at what these and other treatments
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can do within the brain, how to treat Alzheimer's disease.
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- Exciting. Thank you.
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I can't wait to hear all about it. Professor Fox,
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do you want to introduce yourself?
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- Yeah, thanks Anna.
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So as Cath said, I work at the Dementia Research Centre,
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which is here at Queen Square in London.
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And we're a clinical centre and a research centre.
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And the clinical service and the research
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are really intertwined,
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and that's always been ethos and our purpose.
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And my research has been focused on biomarkers and imaging.
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But also about how we can bring forward the search
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for effective therapies and then deliver them.
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And it finally finds,
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it feels like all those bits are coming together.
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- It really does. It really does.
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Thank you.
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And finally, professor Hardy,
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would you like to introduce yourself?
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- Hi. Yeah.
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Nice to be on this call. I'm just across the square.
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I am looking out of the window
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at the building with Nick and Cath in it.
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I work very closely with them. (laughs)
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I work very closely with them. I'm a basic scientist.
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I'm a geneticist and I work on the genetics of the,
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actually I work on the genetics of the patients
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who come into the Dementia Research Centre
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and that's really how this story started.
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- Well, thank you so much, John.
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(logo chiming)
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Well, this is such a big topic,
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but perhaps first and foremost,
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we need to understand what this thing amyloid is
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and what role it plays in Dementia
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and perhaps Professor Hardy, you could start us off.
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- Yes.
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So when you look at the brain
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of somebody with Alzheimer's disease,
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what you see is you see two types of histopathology,
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two types of microscopic pathology.
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You see amyloid plaques,
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they are rather cotton wool like lesions in the brain.
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They're about a 10th of a millimetre across,
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and they're made up largely of a peptide
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called the amyloid peptide.
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You also see inside nerve cells, you see tangles,
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which are made up of the tau protein,
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gumming up, if you like, the neurons.
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Besides those two elements of the microscopic pathology,
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you see neuronal loss, the ventricles that are enlarged.
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The hippocampus in particular is shrunken,
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but the shrinkage all over the brain.
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So you see, that's the pathology.
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And if you like, the thing that turned out
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to be very important in this is that we had a family
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who came into the precursor of the Dementia Research Centre
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where many people were affected by disease.
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And in that family,
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actually the family still comes
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to the Dementia Research Centre.
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In that family, we found mutations in amyloid.
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And that allowed us to say, really for the first time,
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the pathology is complicated,
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but we know in that family it starts with amyloid.
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And the simplest, if you like, generalisation,
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is perhaps it starts with amyloid in everybody.
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So that was the breakthrough that started this really.
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- And I still have in my office, Anna,
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the letter which starts saying,
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and I do this as it's a lovely historical artefact.
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A really important one.
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But it's also a reminder of what we do and why we do it,
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because the letter starts Dear Dr. Hardy,
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who was a mere doctor then I think John,
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two or three lines down in the letter it says,
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"I think my family could be of use to the research."
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And she was absolutely right, wasn't she, John?
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- Absolutely really and a remarkable woman.
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- Yeah. Why is that in your office, Professor Fox?
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And not in.
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(all laughs)
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- Because we have in the room next door,
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a whole series of,
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we still got the paper beautifully labelled files,
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and there's a family file which has all the correspondence
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for each and every one of the families who've contacted us.
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And they started at number one.
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And we're I think we're 600 or something now.
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And this was family 23,
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and it was called Family 23 because it was the 23rd folder,
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literally the 23rd folder,
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which had all the details of the family in there.
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- Gosh.
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- We have all the high tech here.
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(all laughing)
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- Actually, it's even the tech is even lower than that
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because they were piled on my desk.
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And in fact, this family were the first to write to me.
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But I'm so inefficient that by the time I replied,
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there were 22 other folders on top of it.
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So actually it should have been family one,
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because the family wrote to us absolutely immediately
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they got the advert.
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- Wow, that's amazing.
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But they weren't family one
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in terms of the world of discovering amyloids.
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So tell me, maybe Professor Hardy,
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you could also fill in our listeners.
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How exactly was amyloid discovered in the very first place?
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- Well actually, amyloid, the protein
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was first characterised by protein chemists.
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Somebody called George Glenner, who did it in 1984.
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He got the sequence of amyloid Colin Masters in Australia
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got the sequence very soon afterwards.
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So we knew the sequenced, the gene was cloned in 1987.
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So the gene was there and known
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to be on chromosome 21 in 1987.
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We did genetic linkage analysis.
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What you're doing in genetic linkage analysis
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is you're getting DNA samples
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from all the members of a family and you're saying,
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"Which bit of the DNA do all the effective share in common?"
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And we found that the bit of the DNA
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that they all shared in common included the amyloid gene.
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So we sequenced the amyloid gene,
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and that's when we found mutations.
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- So that is a short history of that work
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just to continue the importance of that particular family.
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So that first lady was the first person to go into a trial
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of a treatment against amyloid
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in people with genetic Alzheimer's disease
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and she did that here.
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And her son is now involved in a prevention treatment trial
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to try and prevent the onset of disease in the first place.
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So they're an incredibly important family.
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They've done so much to help us.
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- And along the way, Carol, this is in the public domain,
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helped us set up our, some of our first support groups on,
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which again, I think speaks
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to the importance of both of the families,
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but also that research can't go ahead in isolation.
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And that research should be much more holistic.
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It should be around supporting families
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and very much a sort of co-creating of that research.
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- Yeah, I'm glad you've said that, that makes total sense.
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But it also illustrates how young this area of science is
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in actual fact.
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I think people presume it's this science
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has been around for a lot longer
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and even maybe presume that we've been exploring treatments
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for a lot longer.
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So we know there are these new treatments.
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I mentioned that in the introduction.
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But Professor Fox,
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could you tell us what the treatments actually do
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and how they work to address the amyloid issue?
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- Well, the treatments you've just described,
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which you refer to as the MABs,
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which mean monoclonal antibody.
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So what what is that that's antibody
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much as we're aware of from immunizations against COVID
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and other things,
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we generate antibodies in response to that.
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And actually this story started with an idea that,
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as John had said,
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recognised that that amyloid was a real culprit.
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And but initially wasn't quite sure whether
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it was a driver or a consequence.
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But the genetic element says,
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"Oh, with this, it must be driving the disease,
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at least in the families."
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But we weren't quite sure
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in the rest of the population then,
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or the Alzheimer population then.
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And so there was the strategy of immunising people
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against amyloid.
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This protein that John talks about builds up in the brain.
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The brain has great trouble disposing of it,
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and it just simplistically clogs things up
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and causes toxicity to the neurons directly or indirectly.
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And then you get that,
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that destruction that John was talking about.
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And so, it started with can we immunise people?
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And that was a remarkable experiment.
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And it showed that in mice a model of the human disease,
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it cleared amyloid.
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And the same thing went into humans
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and they got tremendous inflammatory response.
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So it was getting into the brain,
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it was doing what it was meant to do,
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but doing it in an uncontrolled way.
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And that set the field back, the trial had to be stopped.
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It was dramatic. It was very worrying for the field.
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And then everything went quiet for a while.
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And then it was restarted with using antibody.
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So you can control how much immune response if you like,
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you get because you're doing that artificially,
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you are not doing an uncontrolled immunise,
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see how much response people generate.
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And that has been,
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while vaccination continues to be a strategy,
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the dominant MABs have been giving people antibodies
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and what they have shown
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using amyloid imaging
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that this really did clear it cleared amyloid,
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which we know builds up over 20 years.
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It cleared it over about 18 months,
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which I still find quite remarkable.
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I mean, it feels like, it's an amazing achievement.
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And those first monoclonal antibodies that were seeming
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and the immunizations, what wasn't clear
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is whether or not that would deliver clinical benefit.
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And that's been the most recent change.
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So they've been refined and they've been generation
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after generation of monoclonal antibodies,
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generation of MABs.
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There will be some more coming along I'm sure,
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but now these ones both remove amyloid
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and have shown for this to first time
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there is a slowing of clinical decline.
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- These MABs can distinguish between harmful amyloid plaques
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and any, I gather there are non-harmful forms of amyloid
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that also exist.
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Can they actually differentiate?
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- So, I can make a start on answering that
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and others can chip in.
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So one of the things that was done when in response
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to the vaccination trial
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was to try and engineer the monoclonal antibodies
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to go after particular types of amyloid,
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but also not to generate a certain type of immune response.
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So you could get the clearance
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without getting uncontrolled inflammation.
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And the different antibodies
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have different selectivity
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for different types of amyloid.
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And in fact, there's a lovely twist to the story,
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which goes back to, to that first,
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almost the first letter that I'm very disappointed
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to know that it was piling up on John's desk.
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But one of these treatments, lecanemab
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came from a finding in a family
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with one of these mutations
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that people looked in the brains
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and in the cerebral spinal fluid and looked
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and a particular type, one of the forms of amyloid
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along the cascade from the gene down to the amyloid plaques
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was thought to be a good target.
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And that eventually led to lecanemab a great story.
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- It is, it's really circular. It's fantastic.
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And that's why UCL
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are so much at the centre of this whole story of the MABs.
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Is that right?
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- Well, I think that's partly right.
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Yes. I think it's a-
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- It's a worldwide, it's a huge effort for everybody.
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I mean, the John contributed phenomenally to the genetics.
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We've contributed in some small way towards imaging
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and the biomarkers.
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And we have contributed particularly through Cath
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to some of the trials.
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But this is a massive effort.
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I mean the number of scientists in industry
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and outside who probably have spent chunks of their careers
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moving these things forward.
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- Yeah there are millions and millions of pounds and hours
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that have gone into getting to where we are now
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and 20 years of a number of lack of success
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and perhaps ongoing debate about amyloid.
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So I don't think UCL could ever claim the entire success,
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but we've been a very important part of that process,
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I think you'd say.
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- But Dr. Mummery, you highlighted,
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we've really just been focusing on amyloid.
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Do these treatments have any impact on the tau tangles
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that Professor Hardy was talking about earlier on?
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- Well, there are some interesting findings
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from some of the more recent trials.
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And a number of these drugs have shown that,
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as Nick was saying,
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they massively reduce amyloid in the brain
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and then some of them associated with that,
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there is a modest cognitive change.
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So they slow decline but modestly.
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If you look at other biomarkers,
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so whether you are looking at tau levels in the spinal fluid
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or in some cases towel levels on pet,
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you can see small changes.
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And with some of those drugs,
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those changes have been significant enough
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to make us think we really need to continue looking at them.
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So yes, they have downstream effects,
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which is what we think means
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that there is disease modification
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that comes from the amyloid lowering.
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But there are of course other ways
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to target those pathologies,
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which I'm sure we'll talk about later.
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- That sounds good.
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But I want to know about the trials.
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So Dr. Mummery, can you tell us what trials
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are happening in the field right this moment
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what happens to these participants
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when they're actually involved in the trials?
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- Okay, would you like to know just about amyloid
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or about the whole sphere? Because there's a lot going on.
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- [Anna] Let's start with the MABs.
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- The MABs specifically, okay.
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So the ones that are shown positive results in phase three,
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will then go through a process of assessment
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as lecanemab has done in the states in different countries.
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And those countries will approve
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or not approve the drug to be used.
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Alongside that,
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there are other ongoing trials
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in perhaps earlier stage individuals.
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So for example, those people
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that don't yet have symptoms
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but have got amyloid rebuilding up in the brain.
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You've also got studies using monoclonal antibodies
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in people back to the story about genetics
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in people with genetic Alzheimer's disease.
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And in them, what we are doing is two things.
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Firstly, as I mentioned, trying to prevent onset of symptoms
19:05
in some and disease even earlier in others.
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And just to come back to Nick's point,
19:12
you have amyloid building up for 20 years in your brain
19:14
before you even get symptoms.
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So if you know you have a genetic risk,
19:20
then you know and you know, roughly when that family
19:23
tend to have disease, starting with onset of symptoms,
19:27
you have a window of opportunity
19:28
to treat before they ever get symptoms.
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And that's one of the things
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we've been doing for about 10 years.
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Now, we are doing that even earlier.
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So people that are 15, 20 years before symptom onset,
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we're going to start giving them an anti-amyloid therapy
19:44
to try and prevent the accumulation
19:46
occurring in the first place
19:47
and actually prevent the disease, which is extraordinary.
19:50
That's never been done before.
19:51
So very exciting.
19:53
These people are in their early 20s.
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This is not a group of people that are in their 70s, 80s,
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these are young people.
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And so they have huge motivation and ambition for us
20:05
to help us to find treatments that work.
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So that I think is a very important area with the MABs.
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Would you agree Nick?
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- Absolutely. And it's challenging stuff to go really early.
20:23
The question that really faces the field now,
20:25
which is so relevant to what Cath was saying,
20:29
is these trials were for typically around 18 months,
20:32
the ones that have shown benefit.
20:35
Now, if we slow disease for 18 months
20:38
and that's it,
20:44
that's better than nothing.
20:45
But that's not what we want to do,
20:47
really want to do is stop it before it even starts
20:52
or show and that that will be another step of the trials.
20:57
Will this slowing be progressive?
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Will it be cumulative?
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Will you continue to get benefit at two years
21:04
if you continue treat,
21:05
would you actually get more slowing
21:09
or is it just a temporary phenomena
21:12
and then the disease carries on the way
21:16
it has done inexorably?
21:19
And to put that in constant context,
21:22
it is remarkable to think that this is a disease
21:25
described 120 years ago,
21:27
but obviously been around for longer than that.
21:29
It has always inexorably gone down through these families
21:34
and affected people at all ages
21:36
with nothing that can slow it.
21:38
So what the benefit from these particular MABs
21:43
will be earlier in disease or later in disease
21:46
or longer duration, we don't know.
21:48
But those are really important questions.
21:50
- One of the things that we have to do, Anna,
21:53
as we start to give these treatments
21:55
is follow people that are on treatment.
21:58
'Cause as Nick said, these trials are limited in time.
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We have some people that have been on extension
22:04
on these monoclonal antibodies for up to 10 years.
22:07
So there is some information starting to come out
22:10
about what it might look like
22:11
for somebody to be on these for a long time.
22:13
But to get the real answer about
22:15
what a treatment does in the real world,
22:17
we have to have registries of those people
22:20
that start treatment and follow them
22:22
and see how they get on, not over 18 months,
22:25
but over three years, four years, five years,
22:27
and work out as Nick said,
22:29
does this continue to build in benefit or not?
22:34
- I think you said earlier
22:36
you are trialling these with people
22:38
who also already have symptoms or as well, right?
22:42
- That's right.
22:43
- So have you been, and you mentioned cognitive,
22:46
the downstream effects.
22:48
So have you, I guess I'm quite interested
22:50
as well in what have been the cognitive impacts?
22:55
What do we see in those clients?
22:57
- So in in the studies that we've had so far,
23:00
there's been a convergence over several trials now
23:03
in terms of the levels of amyloid removal,
23:06
but also the levels of cognitive benefit
23:09
we see in that period of time.
23:12
And so if you take the 18 months
23:14
and you look at the trials that have shown benefit so far,
23:18
it's around 25 to 30% cognitive slowing.
23:21
So as Nick said, it's not stopping it.
23:24
It continue to decline on average,
23:27
but at around 25 to 30% slower.
23:30
And what that means in the real world, if you are a patient,
23:34
is if you are over 18 months, you are on the treatment,
23:38
you've got maybe around five months extra
23:42
at a higher level than if you are not on the treatment.
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- [Anna] Yeah.
23:46
- Does that make sense?
23:47
- Yeah does make sense.
23:49
I guess it sounds,
23:52
I think Professor Fox kind of emphasised that,
23:54
it doesn't sound like heaps at the minute, but it's huge.
23:57
I mean, I'm wondering what the scale of the,
24:04
I guess what the most significant findings are so far.
24:07
What do you think is like, and how is that gonna develop,
24:11
do you think?
24:12
- The fact that we can change the course of the disease
24:16
at all is that means
24:20
that this is a proper turning point, right?
24:22
That okay, it's a modest effect, but it's an effect.
24:26
And we've had nothing for decades.
24:30
So that will reinvigorate the research world.
24:32
It provides hope.
24:34
It increases people's interest and commitment
24:37
in this sort of research.
24:38
And it's our foundation, this is the foundation
24:40
on which we build better MABs, other drugs,
24:45
different targets,
24:47
and we can now put those stepping stones in.
24:49
So I think that's the biggest thing
24:51
is that we've shown a change.
24:54
- Yeah, I completely agree.
24:56
The analogy I like to use is,
24:59
who would've believed if they watched the Wright Brothers
25:01
on that North Carolina beach,
25:04
that when they got that sort of modified bicycle,
25:07
that this was gonna be the start of the time
25:10
when we could fly.
25:11
But what they showed is you could get heavier
25:15
than contraption off the ground.
25:21
And that led other people to do better later.
25:24
And we had flights from London to Paris, 15 years later.
25:30
And I think it, as Cath is indicating,
25:33
this is where we are, we know what we need to do,
25:36
and the drug companies know what they need to do.
25:39
And the argument about whether this is a good target or not,
25:42
that argument is over.
25:44
So it that unifies the field.
25:47
So all of these things are gonna make things better.
25:52
No doubt.
25:53
- Although you do still get jet lag when you fly.
25:56
So I'm just curious,
25:58
let's say jet lags the side effect of the Wright brothers
26:02
at work.
26:03
What might be the side effects?
26:05
Or are there any other unexpected outcomes that you-
26:08
- That was a contrived link there.
26:12
- That's nice segue.
26:14
- Well, there are, and Nick's the Wright person
26:16
to talk about this because the side effect
26:19
is called amyloid related imaging abnormality.
26:23
And Nick is the imager part excellence.
26:27
And what happens is the first thing the antibodies hit
26:32
is amyloid in the blood vessels
26:34
and they cause inflammation in the blood vessels.
26:37
And that's a problem.
26:38
I'll let Nick do this
26:39
because he knows what he's talking about on this topic.
26:43
- And I'm making it up as I go along.
26:46
- As John said, these antibodies are removing amyloid
26:53
from the brain and from the blood vessels.
26:56
And as they do that,
26:57
it's not a some sort of very simple dissolving
27:05
of these proteins miraculously,
27:08
that involves recruiting our body's immune system.
27:13
It involves inflammation.
27:15
You are removing amyloid, which has been incorporated,
27:19
as we said, over 10, 20 years.
27:23
And that amyloid is within blood vessels.
27:26
And as it gets removed,
27:28
particularly if it gets removed very quickly,
27:31
those blood vessels can become leaky.
27:33
There can be areas of poorly controlled inflammation.
27:37
So there are two types of ARIA, nothing to do with jet lag,
27:42
amyloid related imaging abnormalities. ARIA E, misspelling,
27:46
it should actually be O which is edoema
27:49
in the American spelling, or H which is haemorrhage.
27:53
And haemorrhage is a bit frightening actually.
27:56
The haemorrhages that we usually see are tiny, tiny, tiny,
27:59
very small amounts they're called micro haemorrhages.
28:03
The inflammation or the edoema bit is a swelling,
28:08
both of which that are important side effects
28:14
of the therapy and predictable to some extent
28:17
that we know that it's a class effect.
28:20
If you stop the treatments, the edoema will go better.
28:26
And in these therapies, again,
28:28
this has been a long period of learning
28:31
and of engineering the antibodies
28:33
and engineering the dosing
28:35
and engineering how you need to adjust things.
28:40
But 80% of people who get these things are asymptomatic.
28:44
So it sounds very frightening
28:48
and clearly in the worst case it is.
28:51
But I think it's fair to say that it isn't something
28:58
that the majority of people experience.
29:01
It's a minority and we've learned
29:04
a lot about how to manage it.
29:05
- Absolutely.
29:06
I think that's absolutely right.
29:07
We, so we know, as Nick said, 80% asymptomatic,
29:11
you stop the drug, they go away, you restart the drug,
29:13
they're fine.
29:14
That's the majority of people
29:15
that have that it's happened to me with
29:18
when I've been doing the trials.
29:20
That's the vast majority.
29:21
- And only a proportion will get these in the first place.
29:23
- Exactly.
29:24
- And that varies by antibody.
29:25
- Exactly.
29:26
And it's, if we're talking about these antibodies,
29:29
then lecanemab,
29:30
the one that's been approved in this states
29:32
has a 12% risk of this happening.
29:35
So while that's a significant risk
29:37
and some of them are higher, it's not everybody.
29:40
The other thing is we can predict that the vast majority
29:43
will happen in the first six months, right?
29:45
At least 80% happen in the first six months.
29:48
So, you know, to monitor really carefully with imaging
29:52
when you're first giving the treatment
29:53
for the first six months, and then it's much less likely.
29:57
And the other thing is,
29:58
and we're working really hard to continue the learning,
30:01
one of the things we know well is that some people
30:04
have a genetic risk factor
30:06
that makes this more likely to happen.
30:09
And so we can help discuss risks with people
30:12
in a more nuanced way
30:14
if we know the different risk factors
30:16
that each individual has.
30:18
So I think we know a lot more than we did
30:21
about 10 years ago.
30:23
We need to continue learning
30:26
and we need to ensure that when we give these treatments,
30:29
we have the appropriate monitor and safety in place
30:32
to pick them up and deal with them the right way.
30:35
- All those genes again, isn't it John?
30:36
- It's the genes again yeah.
30:38
- Yeah. We have to, this is a problem.
30:42
We are really working hard to understand better of course.
30:46
And if we could understand it better,
30:49
I'm sure we could find other ways around it.
30:53
- Yeah, yeah, that makes total sense.
30:55
So I confess, I mean I get frequent questions from patients
30:59
and people I meet in my research about these trials.
31:06
And I guess the most common question
31:08
is they ask me about how they can get involved.
31:11
So they're even asking speech therapists
31:13
about how they can get involved.
31:16
So can you tell us and the listeners
31:18
who might be eligible and whether or how people
31:21
get involved with these studies?
31:23
- Yeah, sure.
31:24
I think maybe I'll start and the others can chime in.
31:27
So in terms of, firstly, in terms of how to get involved,
31:30
because everybody can get involved in some ways
31:34
in Dementia research and everybody
31:36
is welcome to get involved, just to put that out there.
31:40
Trials are a more specific and more demanding thing,
31:43
which I'll come to in a second.
31:45
In terms of generally wanting to get involved.
31:48
Then there's joint Dementia research,
31:50
which is one way nationally it's a matching,
31:53
it's like a dating match.
31:56
- [Nick] For the UK.
31:57
- For the UK the whole of the UK.
31:59
So if you're interested in research in Dementia,
32:02
you join up with joint Dementia research
32:04
and they'll match you up with different studies
32:05
and potentially trials.
32:07
That's one way.
32:09
Then there's another portal where it's NIHR portal
32:14
where you can go on and it says, find my research.
32:16
And again, that's a relatively new way
32:18
of working out what's happening,
32:21
but I think what you are making the point
32:23
that they're coming to you and asking about trials.
32:24
I do think it's still difficult
32:26
for people to access that sort of information.
32:29
And we're working really hard
32:31
on trying to make that access much easier
32:35
for our site particularly,
32:37
basically if anybody wants to know anything
32:39
about what we do, they just should get in contact
32:41
and we are very happy to talk to absolutely anyone,
32:44
but it needs to be easier.
32:45
I completely agree with you.
32:46
And we need to work harder on making it easier for patients.
32:50
In terms of who can get into trials,
32:53
typically trials for disease modifying therapies
32:56
tend to be done in people that have relatively mild disease.
33:01
Now, a lot of that is because these treatment trials,
33:04
they require a lot of commitment.
33:06
You need to understand what's going on.
33:08
You need to be able to be comfortable
33:10
with the sorts of investigations
33:12
and assessments you are having.
33:14
And that isn't for everybody,
33:15
but some people find it a really positive experience
33:17
and we support them through that.
33:21
So I think if people have a diagnosis
33:25
and they're interested, the first thing they should do
33:28
is ask the question about who to talk to.
33:31
And we would then go through a process with them
33:35
of making sure that it was the right thing for them,
33:38
that they understood what it needed
33:41
and also that they would be eligible
33:43
or likely to be eligible for the trial.
33:46
Once you're interested in a trial
33:47
and if you have signed up to be involved in that trial
33:50
and you've gone through all the information and questions,
33:53
then what happens is there's a process
33:55
of different tests that you go through
33:57
that make sure that it would be safe for you,
34:00
that you have the disease we think you have
34:03
and that the treatment will potentially help you.
34:06
So that's what we do.
34:08
- Well thank you Professor Hardy, Professor Fox.
34:10
Do you wanna add anything to that?
34:12
- Well, I just to say that the only
34:15
we've talked about all the huge work
34:17
that scientists have done,
34:21
whether it's in design therapies
34:23
or understanding the disease process,
34:27
the ultimate is does it work in people?
34:30
And none of these studies will be possible
34:32
without the generosity of people who take part in research.
34:34
So people saying to a speech therapist,
34:37
how can I get involved
34:39
is exactly what we would like to happen
34:42
and we should make it that every clinical contact
34:46
should be able to say,
34:49
"Yes, I work in the centre or this is my local centre,
34:53
this is the local trial.
34:55
Please do get involved.
34:57
And we've seen the progress
34:58
that's been made in other disease areas.
35:00
You know the percentage of people historically
35:02
that went into trials for Alzheimer's disease
35:04
is a tiny, tiny fraction of the total huge burden
35:09
in the population.
35:10
In other areas, some of the childhood cancers,
35:13
they expect 50% of all people
35:16
with that condition to go into a trial
35:18
and that transforms things.
35:21
- I was just going to say,
35:22
I think that's an absolutely fundamental point,
35:24
but you should have access to research
35:28
at the point you enter a clinical system
35:31
and everybody you meet
35:32
should be able to tell you what's available.
35:34
Everyone, whether it's the porter,
35:36
the speech and language therapist, whoever.
35:38
So if we can get to that stage,
35:40
that would be nirvana, brilliant.
35:43
- It links back to the,
35:44
I did a podcast a couple of weeks ago
35:47
where we talked about justice, about recruitment.
35:50
So many of our listeners might go and revisit that podcast.
35:54
But that's the point we made that research
36:00
isn't currently routinely offered in clinical settings.
36:04
Whereas in other disease groups
36:06
it's often something people expect to talk about
36:09
in all their healthcare encounters.
36:11
So yeah, that would be I an ideal situation.
36:14
So the other question I get to ask,
36:18
and we haven't really talked about this yet,
36:20
is when do you think we can expect these treatments
36:26
to be in use in the NHS?
36:30
I dunno who to start with.
36:31
I think that's the million dollar question.
36:33
- I was on a meeting this morning where this came up,
36:36
so I might start with that and then see
36:38
then the others can challenge me.
36:40
How's that?
36:41
So I was talking to NHS England this morning
36:43
and their estimation
36:45
in terms of the processes that happen in the UK.
36:48
So obviously this has to go through a regulatory process
36:52
and the first part of that
36:53
is the medicines Health Regulatory Authority
36:57
approving the drug for the UK.
37:00
Once that's happened, if that happens
37:03
and I think it's likely that will happen,
37:05
then it goes through the nice process.
37:07
So this is this assessment of not just effectiveness,
37:10
but also cost effectiveness or efficiency, sorry.
37:15
And so that process according to the individuals
37:20
I was talking about this morning
37:22
is currently started and they think
37:25
that process will finish for lecanemab in the summer.
37:30
So summer 2024,
37:31
they expect to have a recommendation on lecanemab
37:36
and for aducanumab they are estimating
37:39
the autumn of next year.
37:41
So that's the hot off the press this morning
37:44
NHS England story, we'll have to wait and see.
37:47
- That's huge.
37:49
- I mean that is a difficult,
37:51
I don't want to belittle the challenges there.
37:57
We perhaps can talk about the challenges
37:59
in terms of how actually giving these drugs in a minute.
38:02
But the challenge from the point of view of getting
38:04
through the nice process
38:07
is that there is no good measure at the moment
38:11
of the burden that Alzheimer's disease
38:14
and other Dementias have in the UK.
38:16
We don't measure it in the right way
38:18
because so many people are doing unpaid care in families
38:22
and so they are struggling
38:24
with how to measure what a drug saves
38:28
and therefore what is worth giving.
38:32
So I think that process will be challenging,
38:34
but it has been done in the states.
38:37
Europe are also doing it at the moment.
38:39
These drugs are the first ones we have
38:41
and we will obviously have to work with them
38:44
to ensure they have the best information possible
38:46
to make those decisions
38:48
and the companies will work with them as well.
38:50
- And what are the challenges
38:52
in delivering it then on the ground?
38:55
- Ah, well we are very lucky.
38:58
We work in a centre
39:00
where we have fantastic multidisciplinary teams
39:03
and we have amazing diagnostic techniques
39:07
and we're used to giving these drugs.
39:09
So, we are able to give these drugs now,
39:11
but if you go to a local memory service,
39:14
they do not have the same sort of level of access
39:17
to those diagnostic tests or monitoring tests like MRI
39:21
and Nick might want to talk about that in a second
39:23
because there are things we need to do to improve that.
39:25
They also don't have infusion suites
39:28
and nurses where you can give these drugs
39:30
and acute hospitals where if something does go wrong,
39:33
you can have the assistance and the treatment you need.
39:36
So right now as a whole in the UK the service isn't ready.
39:41
And what we're doing and working really hard to try
39:44
and help NHS England with and groups across the country with
39:49
is understanding what we need to put in place
39:52
so that services are ready in terms of staffing,
39:54
in terms of diagnostics and in terms of new ways of working.
39:57
I mean, Nick, do you want to talk about MRI for example?
40:01
- Yeah, I think this is gonna be a major, major challenge
40:04
to health systems around the world and the NHS already,
40:11
let's say stretched to be kind,
40:15
will find this a real challenge.
40:19
And a real tragedy for equity would be if this only becomes
40:25
something that's available to those people
40:27
who can pay for it.
40:31
So it will transform the pressure and timeliness
40:44
of diagnosis or the need for that because historically
40:49
it hasn't mattered very much.
40:51
You hadn't, didn't lose time.
40:53
So we've seen that transformation in cancer
40:56
where time was of the essence.
41:01
And now, we may be in a situation where time is brain,
41:06
if you like, the delays in diagnosis
41:08
will cost you brain cells.
41:10
- [Cath] Like stroke.
41:11
- And with a relentless
41:15
and progressive neurogenerative disease
41:17
like Alzheimer's disease,
41:18
this is something that not just that is progressing,
41:22
but it's gathering momentum
41:24
and it's impact across the brain is spreading
41:28
and accelerating.
41:30
So time it will be important
41:31
to be able to make a diagnosis
41:32
and most people never get a very precise diagnosis
41:38
around the world.
41:38
But even in places like the UK,
41:41
so we will have to gear up to make a more secure diagnosis,
41:46
which will mean amyloid PET scan or lumbar puncture
41:50
or potentially in the future a blood test
41:52
and we'll have to make a secure diagnosis.
41:54
But that's only the first half of the challenge.
41:58
We talked earlier about these side effects,
42:01
which if picked up you stop dosing or you slow dosing
42:04
and you can manage them,
42:07
we will need to monitor for these things.
42:09
So in some of the trials people might have many MRI
42:13
magnetic resonance imaging, brain scans
42:16
throughout regular intervals
42:19
and they certainly will need to be able to have it
42:22
if there was any sign of something not being right.
42:25
So this, that might take up a number of weeks
42:29
of the total UK MRI capacity
42:33
if everybody who was eligible was put on a drug tomorrow.
42:37
- I should say, I think that one of the beneficial effects
42:42
already of these drugs even though they're not approved yet,
42:47
is they're kick-starting the process
42:51
for better Dementia care in the UK generally.
42:54
So there was the sense I think that if someone had Dementia,
43:02
it really didn't matter how quickly diagnosis was made
43:06
and it really didn't matter matter what diagnosis
43:09
was made if it was accurate or not,
43:11
because there was almost nothing that could be really done.
43:15
Now that changes that perception
43:18
and now we have to pull our socks up clinically
43:22
and it's easy for me to say as a PhD,
43:25
we have to pull our socks up clinically
43:29
to make the service better, not just for these drugs,
43:32
but for the drugs that are coming down the line.
43:35
- Yeah, and I guess I've also thought about
43:38
the fact that if you were giving drugs to people
43:40
and they've already developed symptoms,
43:43
so the non-genetic types that we might be in a situation
43:49
where that whilst people are gaining six months or so,
43:54
they might need other therapies outside of pharmacological.
43:58
And so I think, so I may be biassed
44:01
as a speech and language therapist,
44:02
but I can imagine that we are also looking
44:05
at adjunct trials in the future
44:07
where you look at the pharmacological alongside
44:11
the say speech therapy or psychological
44:13
or occupational interventions and the broader advantages.
44:17
This is all very exciting,
44:18
but I do have some more questions.
44:21
So I'm gonna start with Dr. Mummery.
44:23
I know this show is all about drug treatments,
44:27
but we can't have you on the show
44:28
without asking about ALN-APP
44:31
and your work on this new type of gene silencing.
44:35
- Okay, well let me take a ti a tiny step back
44:38
from that Anna to, to gene silencing in general
44:40
because I think one of the thing,
44:43
if I may, one of the things that we talked about,
44:46
anti-amyloid monoclonal antibodies only so far,
44:49
and just to take a further step back, actually,
44:52
there are 141 different therapies being looked at right now,
44:56
141, that's brilliant.
44:57
But look at cancer, thousands.
44:59
So we've got a way to go, but it's brilliant
45:02
and it's a lot more than it used to be
45:04
and only 16% of those this year
45:07
are in anti-amyloid therapies.
45:08
That means there's a lot of other things
45:10
being looked at in addition to amyloid.
45:13
And that's important because it's a complex disease
45:17
and we need to look at amyloid in conjunction,
45:19
I thought you were gonna mention it earlier
45:21
with other therapies so that we can try
45:24
and combine things potentially
45:27
to enhance that slowing of disease
45:29
or potentially halt it, right?
45:31
So just to take that step back,
45:33
one of the things we are looking at now
45:37
is instead of using antibodies to try
45:39
and mop up these proteins in the brain amyloid and tower,
45:43
the two that you've mentioned,
45:46
we're trying to work upstream.
45:47
So coming back to the genetics, again, back in that circle,
45:51
what happens if you target the gene that produces
45:55
that protein and reduce its ability to translate
46:00
into the protein and therefore reduce
46:03
production of the protein in the first place?
46:06
Okay, so working far upstream of mocking is deposited
46:11
and you mentioned the ALN-APP drug,
46:14
and that is one that we've been looking at very recently.
46:18
That is an anti-amyloid drug.
46:21
And what it does is it targets
46:24
the amyloid precursor protein gene.
46:26
So this is upstream of amyloid production
46:29
and tries to reduce it by interfering
46:33
with the natural cell process.
46:35
It tries to reduce the messages coming
46:37
from that pro that gene and their translation is the protein
46:40
that work is currently involved a phase one safety trial,
46:46
and I think we now have 26 people in the world
46:49
in that trial.
46:51
So far it's safe and so far the interim results suggest
46:56
it's promising that it's doing what we want it to do,
46:59
which is reduce the proteins
47:02
that are being produced from that gene.
47:03
But it's very, very early days.
47:05
But the one other that I wanted to come back to
47:07
and mention that's not amyloid is against tau
47:10
is the most advanced gene silencing treatment
47:13
we've got in Alzheimer's disease.
47:15
And that treatment, again, it silences the gene
47:19
in a slightly different way.
47:20
It's an antisense oligonucleotide.
47:22
So instead of targeting the cell's own machinery,
47:26
what it does is effectively it prevents the mRNA,
47:29
the messenger from the gene being translated in the protein.
47:34
And that has now completed a phase one trial.
47:37
So it's gone into a bigger phase two trial
47:39
with 700 odd people in the first trial was 46 in the world.
47:44
And it has shown its safe
47:46
and it has shown that it does what it says on the tin,
47:49
it reduces tau in the spinal fluid and in the brain.
47:54
And coming back to what we said before
47:56
about anti amyloids and reducing tau,
47:58
this drug looks like, and it's early days,
48:02
we need to validate this looks like it reduces tau
48:04
in the brain much more than those other drugs did.
48:07
So it might be a good one for combination,
48:10
but like I said,
48:11
we have to wait and see what the later trials show.
48:13
But that's the gene silencing Alzheimer's story
48:16
at the minute.
48:17
- In a nutshell. Thank you so much Dr. Mummery.
48:20
I feel like we need a series of podcasts
48:23
all about these exciting and promising interventions
48:28
and I know they're also,
48:30
I mean, there's gonna be challenges ahead
48:31
despite this exciting stuff going on.
48:34
So just before we finish,
48:36
I wonder if you could just comment on either what you are,
48:42
perhaps both what you are excited about for the future,
48:46
just the thing you're most excited about and the thing
48:48
that you see as the biggest challenge
48:50
or controversy for the future.
48:54
Perhaps Professor Hardy, you could go first.
48:57
- Well, the challenges
48:57
I think are the ones we just talked about
49:00
organising health systems here in the UK
49:03
and around the world. That's challenge number one.
49:07
A challenge two,
49:08
I think is getting better at early diagnosis.
49:10
And here we're very, very fortunate in having I think,
49:16
the best fluid biomarker lab in the world.
49:21
Actually it's in this building in the lab next to me.
49:24
We're very fortunate and I think that fluid biomarkers
49:28
together with imaging are gonna be absolutely crucial
49:31
and we're very fortunate to be able to do that.
49:35
But getting the biomarkers,
49:37
getting better at early diagnosis
49:40
is gonna be a real challenge I think.
49:43
- Yeah, okay. That makes sense. Thank you.
49:45
And let's move on, Professor Fox.
49:48
- Yeah, so I agree delivery and equity.
49:52
I think it's gonna be very challenging.
50:01
The people with Dementia are already isolated
50:06
and disadvantaged or their families are hugely,
50:09
if now that within that group you have a sense
50:14
that you may be missing out on a therapy.
50:17
I mean, that is tragic and wrong.
50:22
I find myself very excited by the thought
50:27
I mean, it's very exciting just to think
50:28
that we are slowing this disease where, which we've watched
50:32
and I have to say, not just because it circles back
50:37
to how you started these questions, Anna,
50:41
I feel a particular excitement about those families
50:46
who've seen this thing come down its generation,
50:48
generation after generation to be able to say,
50:51
"Actually we could stop this gene doing this to you
50:56
or to your children."
50:57
- Actually worth saying, Nick,
50:59
just that when we found the mutation at first,
51:02
Carol Jennings, who we've discussed, said,
51:05
"I don't think this is gonna help my generation,
51:08
but I do hope it helps my children's generation."
51:13
And at the time I would've said,
51:15
"Yeah, we're gonna get sorted in a few years."
51:19
But actually Carol was more realistic than I was.
51:25
And I do think that we are gonna be able
51:28
in the next generation of families, and like Nick said,
51:31
a lot of the next generation
51:34
are coming into to the clinics here now.
51:37
We will be able to do something for the next generation.
51:40
And that is very rewarding.
51:42
- I agree with everything the others have said
51:46
in terms of the challenges.
51:47
I suppose one particular element
51:50
that I think we are gonna have to learn in Dementia
51:53
that we just haven't had to do before, which is great,
51:56
but it is going to be a significant challenge,
51:58
is having discussions with people discuss about risks
52:01
and benefits of treatments
52:03
and making sure we manage expectations
52:05
and give people the information in the right way.
52:08
That's a big challenge when people, as John said,
52:11
haven't even been diagnosing anything other than Dementia.
52:14
So that's gonna be a major shift
52:17
in the way people manage things.
52:18
In terms of what I'm really excited about,
52:20
I mean, I'm biassed,
52:21
but I am really excited about genetic therapies
52:23
in all their different forms, in both genetic diseases
52:27
and in sporadic.
52:28
And the reason for that is, if you look at things
52:30
like the spinal muscular atrophy story,
52:32
that we've seen people, effectively, it's a genetic disease,
52:36
but effectively it is being cured
52:39
by giving treatments early enough and in the right way.
52:42
So I think that's super exciting.
52:44
And the final thing that I've had to do recently,
52:49
and it's an amazing feeling,
52:51
is if you give a drug
52:52
that you know makes a difference to someone,
52:54
which is what I've been doing with lecanemab
52:56
recently in one of the trials,
52:58
that's a really great feeling for them and for you.
53:01
And that's got to be something
53:03
that I find unbelievably exciting so.
53:07
- Yeah, it's super exciting.
53:08
Well, if you need any help writing those consent forms
53:10
in an accessible, language, cognitive, friendly way,
53:16
give me a shout.
53:18
But I'm afraid this is all we have time for today.
53:21
So if you just can't get enough of this topic,
53:24
visit the Dementia Researcher website
53:27
where you will find a full transcript,
53:30
biographies on our guests, blogs,
53:32
and much, much more on the topic.
53:35
And I'd like to thank our incredible guests,
53:38
Dr. Cath Mummery, Professor Nick Fox,
53:41
and Professor Sir John Hardy.
53:43
Thank you for coming.
53:44
I am Dr. Anna Volkmer
53:46
and you've been listening
53:47
to the Dementia Researcher Podcast.
53:50
Goodbye everybody.
53:51
- Thanks Anna. Bye.
53:53
- Thank you. Bye.
53:54
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53:55
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53:56
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53:59
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54:00
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54:03
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54:06
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54:10
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54:12
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54:13
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54:16
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