Podcast – Alzheimer’s Research UK Drug Discovery

Voice Over:

Welcome to the Dementia Researcher Podcast, brought to you by dementiaresearcher.nihr.ac.uk, a network for early career researchers.

Megan O’Hare:

Hello and welcome to another episode of the dementia researcher podcast today I’m delighted to be joined by a panel eager and willing to talk about the dementia consortium and early dementia drug discovery and provide their perspectives from academia and industry. A survey from Novartis, Amgen and Banner Alzheimer’s Institute from September last year showed that 91% of people from around the world believe medical research will result in a treatment for dementia. The study also showed that 60% of those adults believe a cure will be developed in their lifetime, so the dementia consortium is here to provide those sorts of answers for us and it is a private charity partnership between Alzheimer’s Research UK, Evotech and the pharmaceutical companies; Abbvie, Astex Pharmaceuticals, E-I, I can’t say that [laughing] – Eisai?, Johnson & Johnson, Lilly and MSD launched in 2013. The aim of the dementia consortium is to accelerate early drug discovery. So our panel today; we have James Connell, a research manager at dementia consortium, Declan Jones, the vice president of the neuroscience, external innovation at Johnson & Johnson Innovation Centre in London and John Isaac, a senior director of the neuroscience, external innovation at Johnson & Johnson innovation centre in London, and Prof Paul Whiting, the chief scientific officer of Alzheimer’s Research UK at the UCL drug discovery Institute. Welcome to all of you [laughing]. Maybe Declan and John; those are quite some job titles you have there, could you talk us through  our background and what it is you actually do with those job titles?

Declan Jones:

Sure so, I’m Declan Jones, so we both work for Janssen pharmaceuticals –

Megan O’Hare:

Oh! Not Johnson & Johnson [laughing]

Declan Jones:

It is, it is Johnson & Johnson’s. So Johnson & Johnson is a company which consists of the pharmaceutical division, which is Janssen and then consumer health and medical devices and so on. So it’s a big life healthcare company but we work in the, we both work for the neurosciences, therapeutic areas of drug discovery for Alzheimer’s disease, neurodegeneration wider than Alzheimer’s and mood disorders. So my background, I’m, I’ve been in the pharmaceutical industry for a long, long time, I actually when I was thinking about this this morning I’ve been involved in the pharmaceutical industry since an undergraduate, I spent a year working in a company called Organon. I, my PhD was part-funded by Glaxo and I’ve probably been in the in in industry SmithKlineBeacham and GlaxoSmithKline and now Jansen for nearly 30 years.

Megan O’Hare:

So, John maybe you can introduce yourself.

John Isaacs:

Yeah, so I’m John Isaac, I’m Declan’s colleague at the Innovation centre for Janssen in London and again so I’ve worked as actually as an academic for a number of years but also worked for the Wellcome Trust and also worked for Pharma, so I was an academic for about 20 odd years; University of Bristol, I was Professor of Neuroscience there and then I went to the NIH in USA, National Institute of Health, I ran a lab there for a number of years and then I worked for Eli Lilly in the UK, running internal research programs in psychiatry and neurodegeneration and I then I worked at the Wellcome Trust for a couple of years as head of neuroscience and mental health, you know grant funding, so it was an interesting different side of the business and then finally most recently, now working for Johnson & Johnson for the last three years.

Megan O’Hare:

Wow, why did you give up academia?

John Isaacs:

Well, I, I mean I was in academia for 20 years and one of the attractions of working for industry is that your ideas and particularly I was working on how synapses, connections between neurons change during development and in plasticity but also how they go wrong during diseases like dementia and the idea with industry was I could come into industry and then use that knowledge to start drug discovery programmes in mechanisms that I understood about.

Megan O’Hare:

So were you doing drug discovery before in academia or that was just understanding it all?

John Isaacs:

No, it was academic, just understanding how the synapses and circuits work but many of the, of the targets for the newer drugs that are being developed are actually synaptic targets that I worked on as an academic.

Megan O’Hare:

What model organisms were using?

John Isaacs:

Rats and mice

Megan O’Hare:

And now…just a computer?

John Isaacs:

Well now I don’t run a lab anymore so you see I work collaboratively with other companies and academics who work on model organisms and other models.

Megan O’Hare:

Ok, great, let’s move round the table to James, welcome, you brought this great panel together today, so I mentioned that you are a? the? research manager at the dementia consortium, is that right?

James Connell:

So my, my job title is Research Manager for Alzheimer’s Research UK but my, my main role is I suppose leading the dementia consortium with the seven pharma partners that we have and our partner contract research organisations as well, and of those obviously, Declan and John are part of J&J as well as the other companies that you mentioned earlier…

Megan O’Hare:

badly!

[laughing]

Megan O’Hare:

Maybe you could list them, correctly pronounce them [laughing]

James Connell:

So, alphabetically, this is going to be a test; Abbvie, Astex, Eisai, Lilly, MSD, J & J, and Takeda. I think that was seven [laughing], if I’ve missed anybody out I apologise [laughing] but, so yeah, so we, the dementia consortium started back in, in 2014 when Eric Karran, who was previous director at ARUK UK, put the dementia consortium together. We also have a number of other initiatives such as discovery alliance and these are drug discovery institutes embedded in UK universities of which Paul runs the UCL DDI and so the aim of all these different initiatives are to fill the gaps that we currently know exist in early-stage drug discovery and target validation for dementia. And, you know, it’s to address some of the challenges that I think exist in, in this space, you know partnering academia with industry I think is key to you know, bringing successful treatments into the clinic in the future. So, yeah, my role, back to the original question [laughing], my role is Research Manager at ARUK, but I lead the dementia consortium.

Megan O’Hare:

And you said the dementia alliance and the dementia discovery institute, they’re embedded in universities, but the consortium is completely separate, is that right?

James Connell:

Yeah, yeah they’re complimentary so the, the drug discovery alliance and the dementia consortium sit in the same space whereas the DDA, is, is funded by ARUK, the drug dementia consortium is funded ARUK and all the different drug companies that risk-share by investing, each one investing in the projects that come into the dementia consortium.

Megan O’Hare:

Oh right, ok, cool. And Paul, hi. You are the Chief Scientific Officer at the drug discovery institute at UCL, could you tell us a bit more about your background?

Paul Whiting:

Yeah, sure. No, I am indeed. So like some my colleagues around the table actually, I, I have gone from the dark side to the bright side. Or from the bright side to the dark side depending on how you look at it, having spent a number of years in, in industry and then in 2015 I decided I needed a change, I needed a new challenge and this opportunity to become the chief scientific officer here at UCL in the drug discovery institute came up and I was lucky enough to be given the position and so we started in, in, at the end of 2015 with just me sitting in an office [laughing] and now four years almost to the day actually, we now have a good team of chemists and molecular biologists, and neurobiologists and drug discoverists who are working very closely with our colleagues here at UCL, our academic colleagues and beyond, and indeed our industry colleagues; we have a collaboration in fact with Jansen on a particular drug target, and our goal is really to take the great ideas that evolve out of and come out of industry, sorry out of, well out of industry maybe but certainly out of academia and then turn those and determine whether or not those are genuinely good drug discovery targets and we’ll come on to that I’m sure in a moment around target validation and then if they are initiate starter drug discovery programme where we can try and develop drugs that we can then move forward for patients living with dementia. So that’s what we here to do.

Megan O’Hare:

Ok, great, well welcome again to you all this is great, let’s maybe go right back to basics, as I was saying before we started recording, I am a basic biologist, but I have never discovered a drug, so maybe Declan and John, you can talk to us about how the process even begins, what makes a good target and also what is target validation?

Declan Jones:

I’m going to leave that to someone, that last question, to some of my colleagues…

[laughing]

Megan O’Hare:

Ok!

Declan Jones:

That’s something that exercises the mind and has done as long as I have been in, in the industry but I mean for us, we have quite a significant internal labs, wet labs and, and, both preclinical and clinical scientists, both, for neurodegeneration based in our main campus in Northern Belgium, so our, so essentially we do the same internally as we do externally which is; how can we look for the science that we think is compelling that actually is, is worth the significant investment it takes to try and find a first of all a small molecule that you might be able to then do some additional chemistry and turn into a drug, and, and maybe take you know, it’s a really, is the science good enough to actually justify what might be ten or fifteen or twenty years of investment and, and will be hundreds and hundreds of millions if not several billions to try and develop a drug so, so really at each stage we’re just taking a bet that that the biology is good enough to justify the risk to go to the next stage and  so on. One, one of the challenges is being how do you validate a target because we don’t, the animal models, because there is no model of Alzheimer’s, there’s no models of Parkinson’s, no real model that actually mimics all the symptoms and the causes and so on. But can you, can you can take ideas from human genetics from human tissue data and maybe try and model some of the hypotheses in the animals or cell systems, and so essentially we, are, our job is really to look, either to develop those things internally or to work with our colleagues in academia externally to try and drive those forward and share the risk if you like and really that’s why the dementia consortium for us is very exciting, we joined quite late, we joined in 2018, but really it, it, it trawls the world if you like for good targets where we can actually develop, share the risk in developing the target validation and maybe develop the early chemistry and chemistry tools to try and build on that target validation and so on. So for us it, it starts with an idea, it starts with a, a, at the early stages of drug discovery look almost identical to what’s done in academia. You know, do you believe the target, can you develop the target, can you, can you convince yourself it’s worth spending a lot of effort on. Then after that it’s becomes down more to medicinal chemistry, developing assays for drug discovery, when you’ve got a molecule then to do the, the toxicology, pharmacokinetics and so on. So, you just generate enough data that you can take the risk at the next stage and justify the investment. But I think at the earlier stages, something like the dementia consortium is, I think, is a fantastic venture. Maybe, maybe, John or anyone to add, Paul from your history in pharmaceutical industry?

Paul Whiting:

I think the whole piece around target validation is, is, a, is really nebulous and it it’s very often hard to get your arms around thinking what it means because it’s not one thing, it’s almost the coalescence of a whole bunch of data from different approaches and you pull that all together and you get that information and then there is almost a gut feeling; does it, does it feel right, does it smell right does this feel like we should be investing in it or is there something missing, something awry? So while we’d like it to be some sort of qualitative tick box exercise [laughing] and you tick all the boxes and away you go. It’s never really like that you have to use your intuition and experience to really, really determine whether or not you want to take something for a further at least, I don’t know what you think John, that’s my kind of take on it.

John Isaacs:

No, exactly, I think it’s a kind, a triangulation of different sources of evidence. I think the other belief in a target, so a target a typically a protein that you want to stick a small molecule onto to change its function, or you might use an antibody to do that or you might want to knock it down or overexpress it with a gene therapy approach. But say it’s a small molecule that you want to stick onto a protein like an enzyme, so the question is, is that mechanism, is it change, is it that change in that mechanism’s function causing the disease that you want to cure. So for example, if it is Alzheimer’s Disease, is that target protein function also driving the disease so one way, one way to answer that is if you’ve got a genetic mutation which changes the protein’s function, and if you have that, if you inherit that mutation, you absolutely get the disease, that’s the simplest target validation and of course, almost it’s never it’s almost never like that, it’s very very rare diseases where you have these inherited mutations, but they’re necessarily very rare.

Megan O’Hare:

Can I just add, is that like Familial Alzheimer’s Disease…

John Isaacs:

Exactly, exactly like Familial Alzheimer’s Disease, yes…

Megan O’Hare:

We talked about that a few weeks ago, yeah…

John Isaacs:

So sporadic Alzheimer’s, there’s genetic risk factors, many of them, they will have small effect size. So what you’ve, you ask the question; what are the genetic risk factors, what is, say there’s one protein or a pathway that’s implicated by genetic risk factors if you asked the question whether genetic risk factors take this one protein or pathways implicated by genetic risk factors and you say we’re going pick one of the proteins and one of the mechanisms in that. So for example, TREM2 is one that’s recently being, there is a lot of evidence that that’s involved in inflammatory pathways in the brain and you ask the question; what’s the, what do you want to do to TREM2? Do you want to increase or decrease it’s function? And when do you want to do it during the disease course. Those are the two key questions, and you typically, as as Declan mentioned, you can’t get that from animal models because you don’t have a disease, the real disease in the animal model but what you can do based on human data, studying human genetics, human brain pathology, maybe induce pluripotent stem cells neurons from humans, develop a hypothesis about the disease and then you go and model that in your cells or animal and say we think that increase or decrease TREM2 function in this period of disease is causing neurodegeneration and that you want to go and drug that .

Megan O’Hare:

I actually have a question about the disease model thing, so there just isn’t an Alzheimer’s Disease model? Because obviously there’s lots of people who have mice who have different genetic knockouts or mutations, and flies and frogs and rats, but…

Declan Jones:

You can maybe, you can model a hypothesis, so you could say, I’m very interested in TREM2 and you could, you could, or I’m very interested in neuroinflammation or the role of the innate immune system and you can maybe, you can model aspects of that in a model or you can take a model where, you know, a tau overexpressing mouse and say how does that effect neuroinflammation. But, but what you’re doing is, I think, for us, we use those as models of a particular scientific hypothesis not of the disease itself.

Megan O’Hare:

Right ok, I had another question about delivery of various drugs that you have; obviously it’s the CNS that’s affected, is this something that you take into consideration as when you’re doing your drug discovery or is this a bit at a later stage and you’re mainly early?

John Isaacs:

No I think it’s a really important question, so so you’ve got o think about if you’re going to, if you’ve got a target that’s expressed throughout the body as well as the brain, if you’re going to make a small molecule hit that target there maybe liabilities, toxicity liabilities of hitting that target in periphery so the ideal target is one that’s only expressed in the brain and the most ideal target is you want to drug a form of that target which is only found in pathology. So an example of that would be aggregated proteins like aggregated tau, which we know, pretty, have a fairly good idea is a bad thing for neurons so if you can selectively just hit aggregated tau and not normal tau, that’s actually would be, is a really good target, people have been working on this for many years, there’s problems with that. But it’s an important question for sure.

Declan Jones:

So I think the advantage of the dementia consortium, and I think of the DDIs as well, is that you have a group of, it’s a collection of academics and ex-pharma scientists and the pharma scientists have helped to deal with these problems and so they come to it with that mindset and then you have the, the, the basic science or the exciting new and novel science from the academic groups. And you can put those two together I think, I think that’s probably the, one of the real advantages. I think probably unique actually? I’m not sure this sort of arrangement exists in other parts of the world.

Megan O’Hare:

You mean for dementia or for any…

Declan Jones:

Certainly for dementia, I’m not aware of a similar consortia?

Paul Whiting:

No, I think hats off to Alzheimer’s Research UK for really driving this innovation both the dementia consortium and also the drug discovery institute’s, the drug discovery alliance. A really novel concepts and ARUK have really led the way in establishing that, and, you know, I think this this is a really potentially really productive path forward to try and develop new therapies.

Megan O’Hare:

So one of the questions I have is what are the risks and challenges associated with drug discovery and that’s sort of an open question but I guess in a way the consortium is helping to overcome the challenge of people working separately, which is always a problem in science, you work separately, you don’t collaborate, then you know, these ideas aren’t coming together so I guess the consortium is overcoming that challenge. But are there other risks, other challenges you want talk about?

Paul Whiting:

It is implicit in the statement, I think the last drug that was developed for Alzheimer’s Disease was in 1992, which would have been Memantine?

John / Declan / James Connell:

Yeah, I don’t think…

Paul Whiting:

And I don’t know how many failures they’ve been since then, I don’t want to bring the whole mood down [laughing] but there’s been a lot. And you know, so that tells you the ultimate challenge is that this is exceptionally high risk and exceptionally challenging stuff but they need the medical need is is absolutely enormous and growing to a scary amount, so therefore we have to do whatever we can to meet that need. And one of the best ways I think we all agree, we might, I think we probably all agree is by, is by sharing the risk and working together so that the, the, the sum is greater than the individual parts. And I think that’s what these initiatives really really try and do.

Declan Jones:

There was a great, a great quote from someone saying ‘let’s gang up on the problem not on each other’ [laughing] and that to me really sums it up and I think that as you said, the ARUK have come up with a way of trying to get people to work together and, and it’s so much more efficient and us all individually trying to work separately and work with, you know fund individual project or have projects internally share the risk and actually share the knowledge.

John Isaacs:

And James does a great job at herding cats in a way…[laughing]

James Connell:

Yeah and I think one of the problems we’ve had in the past is that academics, you know, the grants that academics, their priorities are publishing, getting further grants, and so their incentives aren’t necessarily you know target validation to the level that industry might do it.

Megan O’Hare:

Because it’s such a long process so having a three year grant isn’t going…

James Connell:

Exactly, and it’s you know maybe beyond their remit if they want to publish something but not necessarily needing to show that it’s involved in human disease for example, so I think the beauty of the dementia consortium is that we have collaboration between dementia experts in industry and in academia. And bringing those two groups together brings you know, synergistic skills and expertise that you know work really well in what we’re trying to achieve.

Megan O’Hare:

I guess I have a bit of a cheeky question maybe? But what is the motivation of a pharmaceutical company to get involved in dementia drug discovery, so you’ve talked about you know, ideas and then you have to invest in, you have to, it’s many years and like Pfizer last year, was it, ended their neuroscience drug discovery programme which would have included Alzheimer’s Disease and dementia drugs, so what is the motivation for a pharma company?

Declan Jones:

It’s hard to talk about whole company, I mean, we’re all, we’re all individual scientists. I mean, my personal motivation is I’ve always, I trained as a neuroscientist, psychopharmacologist, I find that whole thing fascinating and I mostly work in psychiatry drug discovery. We’re making some progress there now, after again years of of not much progress. But it’s very very clear, and I’m also get to the age where there may be some personal imperative [laughing]…

Megan O’Hare:

Knocking on the door…

Declan Jones:

In finding new treatments for dementia, so, so personally I find it, I find it fascinating. For us within our company, we, we, you know, it’s not an easy argument to make because this is an incredibly expensive, incredibly risky operation and so we have to just, we always have to justify say, we believe that the science will justify significant investment and it’s always based on the science because if the science isn’t moving on then there is nowhere, it’s impossible to develop drugs if the science isn’t progressing. So our role, one of our roles in London is actually to help, work with UK academics, academia is very strong, you know we’ve heard about the dementia consortium, the drug discovery alliances, we were able to help create a venture fund to help fund translation to new company start ups and so on to, to really build on the strength in neuroscience in the UK and so on. So there is, there is a real strength and I think it’s a way of actually just energising that and getting people, people to work together. And then and then that helps us to prove that the science is moving along and justify within our own company that this is a, this is a mission worth undertaking. And I think, so for us it’s a, it’s a personal endeavour but it’s also, you know we work for people that who are very driven; psychiatrists, neurologists who were very driven by the patient need, but we also have to justify this significant investment.

Megan O’Hare:

Yep, so this is sort of what you were, Paul, were talking about, about the last drug that was approved was in the 90s and how this year alone quite a few phase II and phase III trials have been discontinued. Can you learn from those discontinued trials, it’s not a waste, surely it’s not a waste. Is that something that the dementia consortium does? I mean surely all drug discovery looks at that?

Paul Whiting:

I think that whenever you do a clinical trial for a new therapy, it’s an experiment. So it obviously, a very expensive experiment and quite a long experiment but it is an experiment, and so inevitably when that experiment fails or even if it is a success you always step back and you try and understand what happened and what you can learn from that so the next time you do it you can do it better and what I think is quite pleasing, that it’s more and more often now, particularly in the dementia field the experiences are being shared across the community, so it’s not being all kept within the pharmaceutical company that happened to run that trial, they’re sharing their experience and what they learnt from that so that we can hopefully do it better the next time and I think, I mean I think there’s a lot of things I think we’re learning about how to treat Alzheimer’s Disease for instance and I think one of the key things, at least in my mind, is that the earlier the better and that’s probably true for almost every disease actually to be honest, but I think we’re certainly learning, that the earlier the better; Alzheimer’s Disease starts many years before you get those first symptoms and so what we, we know is in an ideal world we may well be treating, starting treatment, 10 years, 15 years, whatever, before we first see treat-er- symptoms in patients. So that to me I think is one of the key, one of the key observations. Now how we do that when we don’t have the diagnostics to allow us to tell, whether somebody has, is going to get Alzheimer’s Disease that’s a whole different can of worms but nevertheless I think that’s one of the key learnings.

John Isaacs:

And it also has pushed the field to look for diagnostics, you know, and again I know ARUK is involved in some of this work as well. That’s a really key thing; could you do a blood test that tells you 10 years before you have symptoms that you’ve got amyloid starting to accumulate in your brain for example for Alzheimer’s or Parkinson’s is the other one, when you have motor symptoms you’ve lost about 70% of your dopaminergic neurons so can you again detect disease happening much earlier before you get symptoms.

James Connell:

And I think, I think if you look at either end of the drug discovery chain, we are learning lots of things, we’re in a learning phase aren’t we so if so for example clinical trials we learnt about new biomarkers or new cognitive tests or the fact that we have to go earlier when we do clinical trials, but from a, from the very first starting point as well we’re learning that you know, that genetic risk factors are simply that, that we need to deconvolute or you know look at the function of the risk factors in cells and then try and work out if they’re going to make good targets that cause disease or if they’re just a by-product of something else that causes the disease, so we’re learning, we are in a learning phase I think for dementia.

Declan Jones:

And I think there is also, the whole public-private partnership in the UK, I think is, there’s almost a joined up series of initiatives from the dementia research institute and the dementia consortium, the DDIs, that venture firm that will fund company formation, but also a dementias platform UK which is to do exactly that, how can you do a better job of the early phase 0 and phase Ib studies. So the early phase 0; how can you define biomarkers, phase Ib; how can you actually test the drug as early as possible. And understand is it getting into the brain, is it having a biological effect? And those are all the things, those are the advances that have been made, I think, so we forget those, we lose those, we lose, we don’t hear about those advances, we hear about the failures but I think the field is moving along, not as quick as we’d like but it is moving.

Megan O’Hare:

Yeah, that’s interesting when you say you only really hear about the failures and that’s true and it can seem quite doom and gloom, but I guess you have to try and take the positives from it, and if there results are still being communicated and you can learn from it, I think that’s sometimes you get the impression that, like you said, pharma keeps it to themselves or they’ll publish it in a very thought out way that [laughing].

Declan Jones:

A few smiles from the panel…

Megan O’Hare:

You know, it is published and then, you’re not quite sure if the results are really what they’re trying to say!

Declan Jones:

Can I counter? [laughing]

Megan O’Hare:

Please please do, that’s why…

[laughing]

Declan Jones:

Actually pharma has a much much better record of publishing, I think it was a recent report of all clinical trials…

Megan O’Hare:

Oh, really!

Declan Jones:

Unfortunately, universities have got a long way to go to actually publish in clinical trial data, so…

Megan O’Hare:

Ok, good to know, good to know…

Declan Jones:

So I’ll just say that

[laughing]

John Isaacs:

But I think, you say, you know it’s not, the failures, the tests are publicised, they don’t get as high a publicity but of course if you read the literature, if you go onto Alz forum for example, you see all this, you see all this progress, so it’s, there is a huge amount of progress, there’s just, when you have a phase III clinical trial that costs $300 million to run and took 5 years total start to finish and it fails, that of course is huge news, and so you only hear those big sort of negative events.

Megan O’Hare:

In the Daily Mail.

Declan Jones:

Again, so there was some good news this week in a company in the US, Acadia, was showing benefit against, at least some symptoms in Alzheimer’s Disease psychosis with a drug which they’ve also shown had some benefit in similar symptoms in Parkinson’s, so again that, that was actually very good news on quite a you know robust study, you know just, up the atmosphere there!

[laughing]

James Connell:

Let’s go back a bit, we do have a big problem don’t we in terms of dementia being the, you know, the biggest health care issue in the world today and clinical trials failing, we’ve had half a dozen this year, base inhibitors, amyloid antibodies that have failed because of one reason or another so we have to think about, you know, the dementia consortium and other initiative like that, we’re trying to from the bottom up expand how we or increase the capacity for different ways of getting to new treatments in the clinic. And, you know, the big question is, you know, what are the main targets, or what makes a good target, what are the key things to target in the diseases that cause dementia. So these are huge problems, and huge questions, that we’re facing.

Megan O’Hare:

I wonder, because you said about, obviously this whole thing is at the beginning you have an idea and you’re all deciding whether it is a good target, whether you should invest in it, and then you hear about the trials failing, is it, and then you say you should increase capacity, is it that you’re just not doing enough trials so, do you see what I mean, so in cancer, it maybe that the same percentage are failing you just don’t know because there are so many more successes?

Declan Jones:

I think that is absolutely correct, and that’s one of the areas, I think we’re working to try and fill, so Paul said, a clinical trial is an experiment, a phase II trial it might cost £300 or £500 million but it’s an experiment, you’re asking the question is this going to work, so how can we do, how can we do more studies in man, in a smaller scale? And that’s something we’re trying to work with, with Dementias Platform UK, how can you do a meaningful study where you can say actually, again demonstrate this drug gets in the brain, I think we’re much better at that than we used to be, but that maybe has a biological effect that you think that will then predict, that is a robust biological effect that maybe on the immune system or synaptic function that you say now I really feel confident that I can test the hypothesis in phase II. In the past potentially, we’ve gone to a phase II too early, and not had that confidence. But all you can do is, what can we do to actually make sure that the phase II is a good experiment. We’ll never be able to ever really predict until, at the moment, we can’t really predict whether it will really work but, but you really want to be able to say I did the right experiment with the right tool compound.

Megan O’Hare:

I just, how much mathematical modelling can be used in this, when you say about predicting, is that, I mean that must be something that can be done?

Declan Jones:

I don’t, I’m not sure about the predicting the biology but perhaps you can do in terms of maybe how to design the experiment but you know, hopefully picking the right subjects or having the right subjects volunteer.

Megan O’Hare:

I guess that’s where the DPUK come in, because they have that massive cohort of very well-defined…

Declan Jones:

Exactly, so again you, again they can use that to say ok can we help that to generate novel targets, novel biology. But also can you actually really characterize a group and say these are, this is the right group of people for my, for my treatment, my potential treatment. I mean, Paul…

Paul Whiting:

If only, you could put it all in a super computer, press the button and it spits out the answer [laughing]. I think we do, we are increasingly using these, the new sexy term is ‘artificial intelligence’, AI-enabled drug discovery and this that and the other. And we are beginning to use those in our, in our, in our drug discovery programmes, certainly to help design better drugs or better potential drugs, but actually, unfortunately it still comes down to experience and knowhow and designing as Dec said, your clinical study so you really, if it doesn’t work, you can walk away and you said actually it was a good experiment, we believe the answer, this mechanism does not work, nobody else waste your time on this mechanism, it’s gone. And I think that while that’s not the most desirable outcome it’s kind of, it’s better than an outcome where you say well we did experiment and boy was that a rubbish experiment [laughing] and we’ve no clue whether or not we’ve tested the mechanism or not and we’ve just spent £20 million so that that to me is the worst outcome. So I think more and more now we do good experiments and I think that’s critically important.

Megan O’Hare:

I actually have a very basic question but if a trial fails is that it, the drug’s shelved, you never hear from you again. Or does the drug come back somehow with another drug is like a co-drug, or is that it it’s just gone out your life?

John Isaacs:

I mean sometimes the drug can be tried in a different indication so there could be reason to believe that it should, say it failed in Alzheimer’s Disease but it may work better in Parkinson’s Disease or ALS or some other indication.

Megan O’Hare:

And that would mean maybe you didn’t have the right people in the drug trial to begin with?

John Isaacs:

Yes, it could be that you’re treating it, you know, you’re looking at, take neuroinflammation as an example, you see neuroinflammation in multiple neurodegenerative diseases and it maybe that the type of neurodegeneration or the type of patients with the drug would be better suited in that patient cohort as opposed to say the Alzheimer’s Disease patients.

Megan O’Hare:

Like in cancer there is a lot, you know, it fails in lots of patients but it turns out they don’t have the right mutation…

John Isaacs:

Yes…

Megan O’Hare:

Or if they do, then it’s vastly improved survival.

Paul Whiting:

I think a lot of these drugs that have failed may well, may well reincarnate themselves in the future as a, as a co-treatment with other drugs, because we’re going to see Alzheimer’s Disease and dementia is going to be multiple, going to require multiple treatments, multiple medicines at the same time so I’m pretty sure some of these will, will reappear again. And the other thing is there is this consortium called the DIAN consortium which is, which is in families, people who have inherited forms of Alzheimer’s Disease, so a number of these drugs have failed in what we call sporadic Alzheimer’s Disease are still being evaluated in this very specific, very well defined population of patients who have genetic forms of the disease. And, and the outcomes of these studies will be in the next couple of years really and that’s going to be really exciting because I think that will tell us also a lot again about mechanisms and disease and targeting specific patient populations.

Megan O’Hare:

Talking about, you were saying about, that maybe we don’t target things early enough, is that that maybe these drugs could maybe be repurposed for something that you take in your 30s to help you know, and over the course of your lifetime you take a variety of different drugs at different stages of your lifetime, I don’t know? Sci-fi!

Paul Whiting:

No, I think, well you think about aspirin now for instance or the statins that people take for cardiovascular disease and cholesterol lowering intuitively why wouldn’t you take the same approach for Alzheimer’s Disease? Of course if you, that requires the biomarker, the elusive biomarker we’ve been discussing, you could, so that you’re giving, you’re giving a medicine to a patient who will, who has the potential to benefit from that therapy, I don’t think you’d just give it, bung it into everybody, because that’s not really ethical.

John Isaacs:

And the safety of the medicine has to be absolutely almost perfect so you can’t, if you haven’t got a disease and you take a preventative medicine then that preventative can’t be having any significant side effects, that’s really, so it makes the bar very high in terms of developing their sorts of drugs. But I agree, I think you could see a treatment where you, you could prevent production of amyloid as the triggering event for Alzheimer’s Disease, which, as Paul mentioned, is probably 10 to 15 years before you see symptoms so if you can identify those people who are just starting that process they could take an anti-amyloid agent.

James Connell:

And a lot of trials have been done in people with mild to moderate AD and it’s obviously too late for, to show any beneficial effect but if, you know, the first depositions of amyloid in the brain are, are the thing that then trigger, you know the various early responses, it’s, it’s getting it to the point where you are treating someone early before there’s any damage, because if you’ve got a failure of damage responses for example, after cells have seen amyloid then there’s no point in clearing amyloid because the damage has already been done, so it’s, you know, obviously diagnosing earlier and treating earlier is key.

Declan Jones:

I mean I think that’s, from all of the failures one of the key learnings is exactly that, it would have been very weird 10 or 15 years ago to try and treat someone who yet had, didn’t have symptoms because we, so we’ve developed the tools to say actually this person, and we had a trial like this, to say that this person has an A-Beta signal but has no obvious symptoms. Now that wouldn’t have been possible 10, 10 years ago, and it wouldn’t, I don’t think anyone would have, would have suggested that was a sensible idea in hindsight, it’s an obvious idea, but you know…

Megan O’Hare:

Yeah it does seem obvious now you say it

Declan Jones:

Yeah but 10 or 15 years ago to say I’m going try and treat someone who has no symptoms of dementia with a drug, and I’m going to treat them for decades, I don’t think that would have, that wouldn’t have flown [laughing], so I think at least there is a fundamental understanding now that that is the way forward.

Megan O’Hare:

So the dementia consortium sounds like an amazing collaboration and it is a source of funding in this vital area so, to those listening who are interested in applying to the dementia consortium, what do they have to do? James, maybe you could…

James Connell:

So I would suggest the best thing to do is to contact myself at Alzheimer’s Research UK in the first instance. We also have a, a quarterly call for proposals and on our website, but you know it is often a good idea to have a chat first just to see what stage your research is at before you apply and if there’s anything we can do or, or help you to make application. So we’ve got a dementia consortium roadshow coming up at UCK on the 19th September, you can register for that on our website, and that will encourage academic and industry partners to come together and network for a few hours, there are some talks from academics. We also have on in Manchester and in October and in Oxford in November as well so, you can register for the different events depending on where you, which university you’re at.

Megan O’Hare:

Ok, great. Well, thank you, Declan, John, James, Paul it’s been really, really interesting and maybe I’ll see you at one of the roadshows. Thank you!

All:

Thank you, cheers!

Voice Over:

This was a podcast brought to you by Dementia Researcher: everything you need in one place. Register today at dementiaresearcher.nihr.ac.uk.

END