Podcast – A Closer Look At Lecanemab Donanemab And Amyloid

Voice Over:

The Dementia Researcher Podcast. Talking careers, research, conference highlights, and so much more.

Dr Anna Volkmer:

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’m 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’m sure there will be two more mAbs 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. Donanemab, lecanemab, and 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. So, let’s meet our guests.

Now it’s my pleasure to introduce Dr. Cath Mummery, Professor Sir John Hardy, and Professor Nick Fox. Hello, everybody.

Dr Cath Mummery:

Hi, Anna.

Professor Sir John Hardy:

Hi.

Professor Nick Fox:

Hi, Anna.

Dr Anna Volkmer:

Hi, Nick. Why don’t you tell us all a little bit about yourselves? So, Dr. Mummery, can you go first?

Dr Cath Mummery:

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 going to 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.

Dr Anna Volkmer:

Exciting. Thank you. I can’t wait to hear all about it. Professor Fox, do you want to introduce yourself?

Professor Nick Fox:

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 our 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 feels like all those bits are coming together.

Dr Anna Volkmer:

It really does. It really does. Thank you. And finally, Professor Hardy, would you like to introduce yourself?

Professor Sir John Hardy:

Hi. Yeah, nice to be on this call. I’m just across the square. I’m looking out of the window at the building with Nick and Cath in it. 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.

Dr Anna Volkmer:

Well, thank you so much, John.

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. Perhaps, Professor Hardy, you could start us off.

Professor Sir John Hardy:

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 tenth 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 are enlarged, the hippocampus in particular is shrunken, but there’s 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.

Professor Nick Fox:

And I still have in my office, Anna, the letter which starts saying, and I do this as a… 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,” he was a mere doctor then, I think, John, and 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?

Professor Sir John Hardy:

Absolutely. Really. And a remarkable woman.

Dr Anna Volkmer:

Yeah. Why is that in your office, Professor Fox and not in…

Professor Nick Fox:

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 I think we’re at 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.

Dr Anna Volkmer:

Gosh.

Dr Cath Mummery:

We have all the high tech here.

Professor Nick Fox:

[inaudible 00:07:24] Anna.

Professor Sir John Hardy:

Actually, 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.

Dr Anna Volkmer:

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?

Professor Sir John Hardy:

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 sequence. 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 affected members 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.

Dr Cath Mummery:

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.

Professor Nick Fox:

And along the way Carol, this is in the public domain, helped us set up some of our first support groups with the… Which again, I think, speaks to the importance 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.

Dr Anna Volkmer:

Yeah. I’m glad you said that. That makes total sense. But it also illustrates how young this area of science is, in actual fact. I think people presume 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. Professor Fox, could you tell us what the treatments actually do, and how they work to address the amyloid issue?

Professor Nick Fox:

Well, the treatments you’ve just described, which you refer to as the mAbs, which means monoclonal antibody. So, what that is that’s an 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 amyloid was a real culprit, but initially wasn’t quite sure whether it was a driver or a consequence. But the genetic element says 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 [inaudible 00:11:38] population then.

And so, there was the strategy of immunising people against amyloid. [inaudible 00:11:46] 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 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 antibodies, so you can control how much immune response, if you like, you get because you’re doing that artificially. You’re 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 these 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… It’s an amazing achievement. And those first monoclonal antibodies that were seeming [inaudible 00:13:33] 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 there’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 first time there is a slowing of clinical decline.

Dr Anna Volkmer:

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?

Professor Nick Fox:

So, I can make a start on answering that, and others can chip in. So, one of the things that was done in response to the vaccination trial was to try and engineer the monoclonal antibodies to go after particular types of amyloids, 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 amyloids. And in fact, there’s a lovely twist to the story, which goes back to 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 at 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.

Dr Anna Volkmer:

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?

Professor Sir John Hardy:

Well, I think that’s partly right. Yes. I think…

Professor Nick Fox:

It’s a worldwide… It’s a huge effort for everybody. I mean, 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.

Dr Cath Mummery:

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 lacks 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.

Dr Anna Volkmer:

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?

Dr Cath Mummery:

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’re looking at tau levels in the spinal fluid, or in some cases tau 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.

Dr Anna Volkmer:

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, and what happens to these participants when they’re actually involved in the trials?

Dr Cath Mummery:

Okay. Would you like to know just about amyloid, or about the whole sphere? Because there’s a lot going on.

Dr Anna Volkmer:

Let’s start with the mAbs.

Dr Cath Mummery:

The mAbs specifically. Okay. So, the ones that have 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 building 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 have a genetic risk, 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 twenties. This is not a group of people that are in their seventies, eighties. 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?

Professor Nick Fox:

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. [inaudible 00:20:48] really want to do is stop it before it even starts, or show… And 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 to treat, would you actually get more slowing? Or is it just a temporary phenomenon, and then the disease carries on the way it has done inexorably?

And to put that in 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.

Dr Cath Mummery:

One of the things that we have to do, Anna, as we start to give these treatments, is follow people that are on treatment. Because 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 them 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?

Dr Anna Volkmer:

I think you said earlier, you’re trialling these with people who also already have symptoms as well, right?

Dr Cath Mummery:

That’s right.

Dr Anna Volkmer:

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?

Dr Cath Mummery:

So, 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. [inaudible 00:23:25] continue to decline on average, but at around 25% to 30% slower. And what that means in the real world, if you’re a patient, is if you’re over 18 months, you’re on the treatment, you’ve got maybe around five months extra at a higher level than if you’re not on the treatment.

Dr Anna Volkmer:

Yeah.

Dr Cath Mummery:

Does that make sense?

Dr Anna Volkmer:

That 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… And how is that going to develop, do you think?

Dr Cath Mummery:

The fact that we can change the course of the disease at all, that means that this is a proper turning point. 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.

Professor Sir John Hardy:

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 going to be the start of the time when we could fly? But what they showed is, you could get a heavier than air 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, 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, that unifies the field. So, all of these things are going to make things better, no doubt.

Dr Anna Volkmer:

Although you do still get jet lag when you fly. So, I’m just curious, let’s say jet lag’s the side effect of the Wright brothers’ work. What might be the side effects, or are there any other unexpected outcomes that… [inaudible 00:26:09]

Professor Sir John Hardy:

That was a contrived link there.

Dr Cath Mummery:

Nice segues.

Professor Sir John Hardy:

Well, there are, and Nick’s the right person to talk about this, because the side effect is called amyloid related imaging abnormality, and Nick is the imager par 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.

Professor Nick Fox:

As John said, these antibodies are removing amyloid from the brain and from the blood vessels. And as they do that, it’s not 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 ARIAS, nothing to do with jet lag, amyloid related imaging abnormalities. ARIA-E, a misspelling, it should actually be O, which is edema 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 edema bit is a swelling, both of which are important side effects of the therapy and predictable to some extent.

 

We know that it’s a class effect. If you stop the treatments, the edema will get 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.

Dr Cath Mummery:

Absolutely. I think that’s absolutely right. So, we know, as Nick said, 80% are asymptomatic. You stop the drug, they go away, you restart the drug, they’re fine. That’s the majority of people that it’s happened to me with when I’ve been doing the trials. That’s the vast majority.

Professor Nick Fox:

And only a proportion will get these in the first place.

Dr Cath Mummery:

Exactly.

Professor Nick Fox:

And that varies by antibody.

Dr Cath Mummery:

Exactly. And if we’re talking about these antibodies, then lecanemab, the one that’s been approved in the 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. 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.

Professor Nick Fox:

All those genes again, isn’t it, John?

Dr Cath Mummery:

It’s the genes again. Yeah.

Professor Sir John Hardy:

Yeah. This is a problem we’re 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.

Dr Anna Volkmer:

Yeah. That makes total sense. So, I confess, I get frequent questions from patients and people I meet about these, 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?

Dr Cath Mummery:

Yeah, sure. I think maybe I’ll start, and the others can chime in. So 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 Join Dementia Research, which is one way nationally, it’s matching… It’s like a dating match.

Professor Nick Fox:

For the UK.

Dr Cath Mummery:

For the UK, the whole of the UK. So, if you’re interested in research in dementia, you join up with Join Dementia Research, and they’ll match you up with different studies and potentially trials. That’s one way.

Then there’s another portal, 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’re 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’re 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 are… 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’re 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. And 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.

Dr Anna Volkmer:

Well, thank you. Professor Hardy, Professor Fox, did you want to add anything to that?

Professor Nick Fox:

Well, just to say that the only… We’ve talked about all the huge work that scientists have done, whether it’s in designing therapies or understanding the disease process. The ultimate is, does it work in people? And none of these studies would 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 this centre,” or “This is my local centre, this is a local trial, please do get involved.” And we’ve seen the progress that’s been made in other disease areas. 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.

Dr Cath Mummery:

I was just going to say, I think that’s an absolutely fundamental point, that 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.

Dr Anna Volkmer:

It links back to the… I did a podcast a couple of weeks ago where we talked about just this, 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 an ideal situation.

So, the other question I get to ask, and we haven’t really talked about this yet, is when do you all think we can expect these treatments to be in use in the NHS? I don’t know who to start with. I think that’s the million-dollar question.

Dr Cath Mummery:

I was on a meeting this morning where this came up, so I might start with that, and 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 that process will finish for lecanemab in the summer. So, summer 2024, they expect to have a recommendation on lecanemab. And for donanemab, 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.

Dr Anna Volkmer:

That’s huge.

Dr Cath Mummery:

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.

Dr Anna Volkmer:

And what are the challenges in delivering it, then, on the ground?

Dr Cath Mummery:

Ah. Well, we’re 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?

Professor Nick Fox:

Yeah. I think this is going to 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 whole pressure and timeliness of diagnosis, or the need for that, because historically it hasn’t mattered very much, you 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.

Dr Cath Mummery:

Like stroke.

Professor Nick Fox:

And with a relentless and progressive neurodegenerative disease, like Alzheimer’s disease, this is something not just that is progressing, but it’s gathering momentum, and its impact across the brain is spreading and accelerating. So, time 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 an 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, 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.

Professor Sir John Hardy:

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 kickstarting 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 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.

Dr Anna Volkmer:

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 maybe the non-inherited, so the non-genetic types, that we might be in a situation that, whilst people are gaining six months or so, they might need other therapies outside of pharmacological. And so, I may be biased 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 their broader advantages. This is all very exciting, but I do have some more questions, so I’m going to 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.

Dr Cath Mummery:

Okay. Well, let me take a tiny step back from that, Anna, to gene-silencing in general, because I think, 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, and I thought you were going to 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.

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 tau are 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? So, working far upstream of [inaudible 00:46:09] deposited.

And you mentioned the Alnylam 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 gene and their translation into the protein. That work has 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 for 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 it’s 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 its 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.

Dr Anna Volkmer:

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 there’s going to be challenges ahead despite this exciting stuff going on. So, just before we finish, I wonder if you could just comment on perhaps both what you’re 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.

Professor Sir John Hardy:

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. 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 going to be absolutely crucial, and we’re very fortunate to be able to do that. But getting the biomarkers, getting better at early diagnosis is going to be a real challenge, I think.

Dr Anna Volkmer:

Yeah. Okay. That makes sense. Thank you. And let’s move on, Professor Fox.

Professor Nick Fox:

Yeah. So, I agree. Delivery and equity, I think it’s going to be very challenging. The people with dementia are already isolated and disadvantaged, or their families are hugely… If now within that group, you have a sense that you may be missing out on a therapy, that is tragic and wrong. I find myself very excited by the thought that we… I mean, it’s very exciting just to think that we are slowing this disease, 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.”

Professor Sir John Hardy:

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 going to help my generation, but I do hope it helps my children’s generation.” And at the time I would’ve said, “Yeah, we’re going to get it sorted in a few years,” but actually Carol was more realistic than I was. And I do think that we are going to be able, in the next generation of families, and like Nick said, a lot of the next generation are coming into the clinics here now, we will be able to do something for the next generation, and that is very rewarding.

Dr Cath Mummery:

I agree with everything the others have said in terms of the challenges. I suppose one particular element that I think we are going to 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 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 going to be a major shift in the way people manage things.

In terms of what I’m really excited about, I mean, I’m biased, 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’s 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.

Dr Anna Volkmer:

It’s super exciting. Well, if you need any help writing those consent forms in an accessible [inaudible 00:53:15] 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.

Dr Cath Mummery:

Thanks, Anna. Bye.

Dr Anna Volkmer:

Thank you. Bye.

Voice Over:

The Dementia Researcher Podcast was brought to you by University College London, with generous funding from the UK National Institute for Health Research, Alzheimer’s Research UK, Alzheimer’s Society, Alzheimer’s Association, and Race Against Dementia. Please subscribe, leave us a review, and register on our website for full access to all our great resources, dementiaresearcher.nihr.ac.uk.

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