- Hilary Evans, Chief Executive of Alzheimer’s Research UK and Co-Chair of the UK Dementia Mission
- Dr Alan Duncan – Clinical Lead and Consultant Psychiatrist for Old Age, NHS Dumfries & Galloway
- Minister’s speech – Maree Todd, MSP – Minister for Social Care, Mental Wellbeing and Sport
- Professor Craig Ritchie – CEO and Founder of Scottish Brain Sciences
Henry Simmons, Chief Executive, Alzheimer Scotland: “Minister that was fantastic, thank you so much and I know the pressure of driving from Edinburgh to Glasgow and if there is an accident it is terrible, but I am sure you will agree colleagues that was really inspiring and rally really thoughtful: the value base, everything was in-line with discussion all day. So minister thank you so much for making the effort to get here. We really appreciate it and we look forward to moving things forward. Thank you. One more round of applause. Thank you. I was in the process of introducing the man who needs no introduction. Sit down a wee minute till I embarrass you for a second, just for a second, yeah. Colleagues, I think you know . . . we are talking about some wonderful stuff today and it’s been fantastic and we have been building up all of the sort of the debate and discussion about brain health being part of Scotland’s National Dementia Strategy: well that’s amazing. I could list a few titles that Craig’s got and I could go through a long list of work the man’s done, but one of the most important things that I will always credit Craig for . . . Craig was the first person who ever spoke to me about brain health and when he came back up to Scotland we met and he started talking about what was possible and started talking about prevention. It was Craig who started talking and mentioning it in that context to me and I think that is something I will never ever not appreciate and forget but I think a lot of what we have been able to do started with that initial return and the discussion and the idea. And then we met with the Government, the First Minister and we managed to get the Government on board, and you know I think that chain that started there has put us at the forefront of the world which is remarkable. So can I ask you to warmly welcome Craig”
Professor Craig Ritchie: “This says 10 minutes, I thought I was going to get 20? I am joking. No, [laughs]. Thanks so much Henry. I also thank Rynagh for her kind words of introduction earlier on [Rynagh Flynn, SDWG].
Em, ergh, ah, there we are, so the, em slightly, eh strange title to my talk, em, ‘Does this new chapter need some new words? Transforming perceptions and management of Alzheimer’s Disease’. If I think back to the time I came back, almost 9 years ago to the day, from London to Edinburgh, to Scotland, em, and came to this Conference. I think back to the kind of conversations that we were having at those conferences: I can almost guarantee that the words ‘brain health’ were never mentioned. I can probably guarantee – well I could guarantee – that ‘blood-based biomarkers’ were never mentioned. I definitely know that ‘disease-modifying therapies’ would not have been mentioned. But here we are now 9 years later and all those words are just tripping off our tongue, naturally. This is the new chapter. And I often reflect on whether [. . . oh, I have been given 15 minutes, thank you]. I often reflect on whether or not those, this new chapter that we described, is a new chapter of the same book? Or is it a new chapter of a new book? Should we be ripping up the old book and the way we have done things in dementia care and neurodegenerative disease over, literally the last 100 years, and start again? From the knowledge that we have now of brain diseases, em, as Alzheimer’s disease with cognitive symptoms rather than cognitive disorder.
So what I want to do over the next 14 or 15 minutes or so is just sort of ask people to reflect as I show you some data from a drug trial and whether or not we do need new words, a new narrative for what we need to do as we go deeper into the 21st century.
I am very proud of the fact that I do a lot of work for industry. Em, John mentioned the Advisory Boards, and I am fortunate I fitted all of those criteria apart from I am still under-60, just. Em, but I do work a lot of . . . and as many of you know I set up my own Company, a year ago, to join other parts of this ecosystem in Scotland: the NHS, the universities, the charities, the third sector. And a commercial company is going to join if you like . . . join this kind of drive to improve access to new therapies and new diagnostics.
So, I am slightly concerned that during the course of the day there has been lots of people saying what Craig’s going to be talking about in his presentation [grimaces to self], but actually [laughs to self] I think I have got a slightly different presentation than the one you were all expecting. Em, I mean, Allan mentioned for instance the blood-based biomarker work that they have been doing in Dumfries and Galloway: the DAVOS Alzhiemer’s Collaborative. Em, and I could, and I will maybe touch on it as I go through the presentation, but incredible innovation, think about it! A blood test for Alzheimer’s disease. And in the near future we are likely to have a blood test for Lewy Body disease. A blood test for Huntington’s disease we already have. So all these things that can be assayed and collected and analysed, and then of course as Allan was mentioning, then disclosed and shared with the person with the symptoms or even better before they get symptoms. How transformative is that! Think about it. You know I could have a blood test for Alzheimer’s disease today, I am 54 years old. I might have very very very preclinical Alzheimer’s disease. OK? I don’t want to wait 20 or 30 years for the symptoms to develop. Wouldn’t it be amazing if I could find out now, especially when there is disease-modifying therapies that are available [laughs to himself] if the regulators and NICE and SIGN approve them . . . to get rid of that amyloid in my brain and in effect [and I say it with great caution] cure me of Alzheimer’s disease. That is the New Chapter. Maybe, as I said, it is a New Book.
So the overview of my presentation is to talk about therapeutics. I have got one particular, I have got a series of slides about a drug called DONANEMAB, a monoclonal antibody drug called DONANEMAB, which I want to use as an illustration of, em, what is going to be possible in the future. But not just use the numbers which I am going to present here in this slide – this slide is really horrible – I have probably given about 2000 lectures in my time and I never learn the lesson of over-crowding my slides – so apology in advance for that. But I am going to show you a lot of numbers. But the really important thing is that statisticians speak to each other in numbers: that is their code, their language. But for most of us normal human beings we need words. We need sentences. We need a narrative. So what I am going to try is to dissect out that difference between the numbers and the narrative. And when I am presenting this data on the DONANEMAB trial, I all want you to think about your current practice, or your current experience with practice: memory clinics and in the not too distant future, Brain Health clinics, and think would this practice be able to accommodate what I am about to show you? Okay?
So, the language of Dementia and the language of Brain Health. The different words we use in each of these, I had actually thought I was going to be first speaker here rather than last speaker and I was going to play a game of lexicon bingo: let’s put some word together and see how often they are used in different presentations? ‘Prevention’, ‘Hope’, ‘Frailty’, ‘Dementia’, ‘Institutionalisation’, ‘Mental Health’. And you probably find them clustering around the brain health presentations and the dementia presentations. The way we think about Alzheimer’s disease in the context of brain health I think is necessarily different to the way we think about it, describe it and talk about it in the context of dementia.
So, here is one of my superbly over-crowded slides, for which I apologise. So what we are going to do is spend the next 6 or 7 slides presenting you with some data from a trial that was recently announced in Amsterdam for the Alzheimer’s Association International Congress, eh, a few weeks ago actually. For the very eagle-eyed on the right-hand-side that’s the actual front of the paper, you will see that I was privileged enough to be flying the flag for the UK as one of the co-authors, and that flag you will be glad to know was a saltire, eh, amongst all the other co-authors mainly based in the US and one from Sweden. From the top left-hand panel, I am not going to spend a great deal of time discussing the biology of Alzheimer’s disease but I think that it is worth noticing that, or noting I should say, that these . . . there are 2 core proteins that are worth considering: amyloid and tau. And what this monoclonal antibody actually does, it targets the amyloid plaque in the brain and very effectively clears it. Now we believe, from that sequence of events in that very top left-hand corner, is that the amyloid aggregation, the gathering of this amyloid together into a plaque is a necessary step before the next sequence, the next pathological process in the sequence which is the aggregation of a protein called tau, which we think really drives the symptoms. Okay. And what this trial was doing was trying to confirm a previous trial, a phase II trial, published 2 or 3 years ago, which showed that this drug DONANEMAB is very effective in clearing amyloid from the brains of the individual. The bottom left-hand panel is demonstrating the fact that we believe that this drug works particularly well at a stage of tau-opathy low to medium term – and this is beginning to get at, again another word that we are going to start using, another concept: precision medicine. These drugs won’t work in everybody. It is not a one-size fits all. We’re going to have to find the right people for these therapies and we are going to have to find them through biological tests.
So, who were the people in this study? Well, em, critically in the orange, they had to have shown evidence of amyloid and tau on brain scans. So if you want to use these drugs in the future we are going to have to know if there is amyloid or tau in brain scans, or possibly as I mentioned through blood tests. And these were people with an MMSE of 28, the people if you like who have what we describe clinically as mild cognitive impairment [MCI] or mild Alzhiemer’s Dementia.
The important thing in this slide – there is a lot on it – but the important thing on this slide for me is that the way this study was set up, was that if you cleared amyloid in your brain as measured through this PET scan, you could stop the drug. [Long pause by presenter]. Now in most other branches of Medicine: cancer, MS, if you clear the disease you are in remission, you stop the therapy. Wouldn’t this be amazing? You clear the amyloid, you are in remission, you monitor overtime to see if you relapse and you start the drug again. So people talk about the expense of these drugs? But this drug may only be a 12 month course and then monitoring thereafter. Again, very different narrative from what we are describing with the use of Donepezil, Memantine for symptomatic treatment.
Important point from this slide is that when they actually looked at the people who were coming through this study – this slide is very busy and I don’t really have a pointer – that of the people who achieved this amyloid clearance, 50% by 1 year, this hypothesis that you could clear amyloid within the 12 month period was proven in this trial. Okay, so this, this, this, this kind of assumption, this hope, this aspiration that you could drive remission was achieved with DONANEMAB.
This is a headline result if you like. How good was this drug at improving symptoms? Or controlling symptoms if you like? Now on the left-hand side we have a scale IADRS and on the right-hand side we have something called the CDR-SB. Now, when we presented this data in Amsterdam, it didn’t happen here [smiles to himself] there was a round of applause. Because this effect-size 3.35 point change on the IADRS and 0.67 change on the CDR-SB is off the scale [expansive hand gestures] from what we have ever seen in drug trials before. This drug didn’t just clear the amyloid, it actually really made a huge impact on clinical symptoms. So by clearing the amyloid – that is all it does – it doesn’t affect neurotransmitters, it doesn’t affect tau directly – all it does is clear amyloid, you see this massive clinical benefit. But the other thing, the other narrative I have from this slide is that if you look at the dark black line on the left there: that is what we call the placebo curve [for people who get saline rather than the active treatment]. Over 18 months look at the decline [long pause by presenter]. In Edinburgh, when I left, the memory clinic the waiting list for was 18 months [smiling]. That’s how much decline happens while people are waiting to see us. I think that is unforgiveable.
And this is, this is another really fascinating piece of the data: for those people who were able to come off the DONANEMAB, about 12 months on average, they still continued to improve over placebo. So you have cleared the amyloid: is the brain recovering? Is the brain able to achieve some degree of, you know, resilience to come through? . . . Because the, the gap, if you like, when they stopped, between placebo and active is 2.68, two weeks later it is 3.10 – they are not on the drug anymore and they are still gaining benefit with 3.52 at 18 months.
Another way to conceptualise this is not just the difference between the two, in terms of the change scores between the two populations on these outcome measures, but how much time is saved? So instead of looking at the vertical, let’s look at the horizontal: time saved with the disease-modifying therapy. In some ways this is probably more important because what we are actually saying is: if I can drive at this time point, what are the chances I could still drive in 6 months? If I can still engage with my grandchildren at this time point, what are the chances that I can still do so in 6 months? If I am still valued by my family, if I still contributing at this time point, what are the chances that I can still do so in 6 months?
The fact is, that over the course of just this 18 month study, you are gaining about 5 months. Now this is only an 18 month study. Who’s to know what will happen in the longer term? Also what will happen, and trials are ongoing in an even earlier population? A pre-clinical population. To see whether or not that time saved might be years rather than just weeks and months.
So this is the data from how much amyloid is cleared in the brain. We don’t have survivors [points at the audience] in this cohort from Alzheimer’s disease as a clinical construct. We have got people cured of amyloidosis. These people don’t have amyloid in their brains anymore. These are, in some ways, survivors. I think if we reconceptualise Alzheimer’s disease as brain disease, rather than a cognitive disorder, we could confidently use the ‘c’ word and say that they are cured. That they are survivors.
Em, what also happens – I am aware that I only have a couple of minutes left – what also happens is, I mentioned before that the tau, a sort of protein, comes after amyloid in this cascade. This drug targets amyloid though the tau levels went down dramatically as well. So getting rid of the amyloid you are affecting the tau which drives the symptoms. It is just incredible.
And the other thing – I will just flick through this very quickly – the take-home message from this is: the effect: 30% slowing, 36 % slowing, 30% slowing, 21% slowing – you get more bang-for-your-buck the earlier you start treating people. So here is another argument for early detection.
Now, safety: there is a condition called ARIA which we know is a condition associated with all of these drugs and needs lots of brain imaging. But we know what to expect and we know how to treat and detect it. We know it happens early. Again, in the clinics of the future, we need to have incredible access to MRI scanning to be able to use these drugs safely.
So the numbers with DONANEMAB: talk about consistent efficacy, better for earlier disease stage, and like I said 50% of Trial participants achieved amyloid clearance at one year. That’s the numbers. What is the narrative? It is early detection [nods]. We heard this morning, from Helen, about brain health clinics. Those aren’t a nice to have. Those are a need to have. We heard from Vivek that the majority of people are still coming in for diagnosis at the mild to moderate stages of disease in our memory clinics. That’s too late, for these drugs. We have to think about these conditions not as mental health conditions, not as psychiatric conditions: these are brain diseases. Now I am a psychiatrist, not a neurologist but we have to think of these things as brain diseases. As Alzheimer would have expected us to. That means that we really have to gear-up our imaging capacity, our laboratory capacity to do blood-based biomarkers, our medical capacity and indeed the expertise, the doctors, the nurses, the allied health professionals, who are working in those brain health clinics. And we have to change the culture away from this kind of palliative care approach we have at the moment for people with symptoms: we are never going to cure, we are never going to reverse these things, that unfortunately things will never go back to where they were. But in this early stage, I think we can optimistically say and confidently expect people to be cured of amyloidosis – amyloid in the brain. There will be survivors. The reason I emphasize survivors is – the main drive [bottom left picture on slide] for the developments and progress made in defeating HIV were the survivor stories. It was survivors who went to Washington, who went to London, who went to Capitals around the world saying: we need to have access to these drugs [repeatedly hammers the podium with hand]. Without those survivor stories our message is a lot weaker. So we have to accept in terms of our attitude, the complexity, embrace it: this is going to be tough, and you know what it is going to be really, really expensive. So what. So we should be. The cost for diagnosis of Alzheimer’s disease is about 50-fold less than cancer. Why is that? Why do we accept that?
My final point [shakes head]. You can tell: let’s not be polite about this anymore. Let’s be very, very angry about our situation. We don’t need science anymore. We have got blood-base biomarkers, we’ve got disease-modifying therapies. Let’s be angry with the people who can make decisions on these things. We want them [the new drugs]. We want the capacity. We want the infrastructure and we want to spend a lot more money on this. I’ll stop there.
[APPLAUSE from auditorium]
Henry Simmons, Chief Executive, Alzheimer Scotland: “Well Craig, thank you so much. That was absolutely fantastic and I am sure everyone will be, like, inspired and a bit angry about that [smiles towards Craig Ritchie]. So thank you.”