Prof Craig Ritchie: Looking Back at EPAD, moving forward in Alzheimer's Disease

Uh, and, and interestingly for today's discussion, he was the chief investigator of EPA d and so that'll be one of our topics today. So welcome to in the interim, Craig.

Um, and there was a whole bunch of reasons back in 2015 when we started the project that we felt there was challenges in developing new therapies and EPA was. Hugely ambitious project that really did in many ways, tried to boil the ocean. You know, we, we wanted to look at recruitment. We wanted to look at early detection of the disease. We wanted to look at new trial designs, which of course you are intimately involved with.

Um, and huge program of research across Europe and with partners all over the world. Um, just to give it a sense of scale, I think at one point there were. Over 400 people working on the project. It was a 64 million euro funded program. Um, and 39 partners from pharmaceutical companies, small medium enterprises, as well as, um, as, as as major academic institutions across Europe.

So yeah, huge, a huge program and like I said, trying to really help develop more rapidly, better therapies for Alzheimer's disease.

They fire the gun and it's as if it's as, it's as if it's the first trial that's ever been done, and you're starting, every time you do a new trial, it's like you're starting from, from, from baseline again. So the readiness cohort was, was, was, uh, a very good, um, uh, program that created readiness. You, you had thousands of research participants who were ready to be involved in a clinical trial.

And the readiness was probably in some ways across two, sort of, you know, um, main, main, main dimensions, if you like. Number one was they, as people were ready. So when they were consented into the cohort study, um, it was very much, this is the intention of the cohort study is if you're eligible and you're, and you're willing to participate, there could and should be a drug trial for you. You at some point in the not too distant future.

So they were adjusted, they were psychologically ready, they were committed to being in a drug trial. And then the other element of readiness was we knew a lot about these participants.

We knew their amyloid status, we knew their cognitive status, we knew their medical comorbidities so that when the trial started or when the trial would've started, we would have a very low screen failure rate because we weren't, you know, again, just going to the community and hoping we picked up a bunch of people with Alzheimer's. Pathology or particular range. So that was, that was the two major, major dimensions of, of readiness.

But like you said, Scott, there was, there was other things came outta that data set, um, that we were, we were, we were collecting, which are, you know, been actually transformative in terms of our understanding of early disease. 'cause one of the, the key things, like you said at the, of the, of the, of the, at the beginning, this was the European prevent prevention of Alzheimer's dementia. So nobody in that cohort had a dementia syndrome at baseline.

These were people who were maybe at high risk of developing the dementia syndrome but didn't actually have it. So this was very much about the earliest stages of the disease and, and, and exactly where people I think want to be treated, you know, before the symptoms start to emerge.

Um, I mean, it was a hu I mean it was in many ways a hugely successful project. Um, um, not just for developing that cohort study, which I think is the largest, um, collection of data and participants. Uh, still to date, uh, with the, the depth and the level of phenotyping. Um, one thing we didn't mention was, of course, that everybody, for instance, had spinal fluid taken an all very detailed brain imaging.

So this wasn't, there were certainly elements of this, which were, um, necessary for, for finding people for trials, but we also had this kind of secondary objective of, you know, really trying to understand the, the upstream disease mechanism.

That drive, um, Alzheimer's disease and, you know, with, with a view eventually, I guess, to going even further upstream with, um, with interventions and precision medicine ultimately around particular individuals in particular, you know, profiles of, of, of disease well before symptoms develop. So, and a lot of the objectives of vpa, if you, if you like, have survived into a lot of programs today.

You know, 'cause I think the, the, the, the gang we had together of academics and industry folks was second to none globally. I mean, there was just the, the thought leaders, the, the passion that was in the program, the early career researchers, it was, it was incredible legacy that our projects had moving forward.

Of, and I, I remember one of the things that we added into the original tender was, was an additional work package work package eight, which was ethics, legal, and social implications. 'cause we did consider that having this approach, which was novel, you know, people still probably still think about Alzheimer's as an older person's disease that affects, you know, people, you know, they're say about to, you know, um, you know, have, have, have problems with driving or or, or day to day living.

And we are courses. Investigators and as companies thought, you know, this is a midlife disease and this is something that, you know, affects people before symptoms develop. So we, we also had to give a lot of consideration to the narrative around what we were doing. So, like you said, we had a system in place where we had participant panels at a site level, at a national level. At international level. We had also lots of press releases with, with participants who'd been involved.

So it was a, it was, it was, it was a, it was a, and we've actually, as you, as you, as you may recall, we've actually published some papers on. Research participants being involved in design and, and delivery of the, the program. So that was a, a huge, um, that stage, quite innovative, uh, wave forward, uh, particularly with this population.

We had a panel, we had the disease modeling, et cetera. Ultimately, this, this didn't meet its primary objective. Um, and I think, you know, the, the, the, the, the reasons for that, and I think we've obviously reflected on this since 2020, um, were that I think it was a big leap, if I can be candid for a lot of the sponsors. To say we trust this platform for how we're gonna develop our new therapy.

Because in many ways, we were asking companies to put in their prized asset, and particularly a biotech, for instance, or even a big pharma, to outsource this in a, in a sense, to a third party to run the study. And I think if, if, and you know, you and I have talked about this a lot, obviously over the years. I think if we could have our time again, it may have been.

Um, useful to sort of put in a repurposed drug as a proof of proof of platform, because I think once we had the data that showed the platform worked the readiness cohort recruited, well then I think this sort of created the momentum, uh, and the, and the, and the assurance that I think people upstairs in these drug companies that we weren't necessarily talking to directly would've had that. They said, yeah, let's go for it.

We were also a little bit unlucky that there were a couple of companies, and I probably shouldn't say who they were because I'm pretty sure it's confidential, but who were gonna, were very committed, but they actually had problems with phase in phase one with toxicity and another thing. So we seemed to have a series of issues that seemed to work against us to actually, um, get a drug in. But I mean, fundamentally, I believe, I think a lot of people did this is this is actually the way forward.

Um, and. Of course 2020 hit, uh, COVID happened and I think a lot of momentum behind the project got, got, got lost a little bit. Um, I think if, if COVID hadn't hit and we hadn't lost that couple of years, then I think we would probably dusted ourselves down regrouped and gone again a lot more quickly. Um, but you know, as you know, I'm trying to, I'm trying to re re-engineer these things again through channel.

These are our work packages, these are our deliverables, etc etc And actually flexing the program in life is really, really hard, if not impossible. So if we wanted to repurpose some of the dare say, if we wanted to move some funding to actually have a repurpose medicine, that was really not really open to us as an opportunity. So even though we kind of. Thought, you know, this would be probably a sensible thing to do.

There wasn't really the mechanism within the trial or within the program to be able to do that. And, and I think the other thing, I mean, it sounds, again very detailed, but the, the way we were gonna sustain the platform was to do the trials so the money was gonna start flowing back into the system because the sponsors would pay for a trial and that would maintain the cohort study, etc So without that trial, then there was no sustainability because the grant finished after five years and.

You know, again, I often, you know, as, as you know, Scott, I've come into the business world and, and you know, you could almost argue there's a 64 million Euro investment, but at the end of the five years it just disappears.

And actually think for all that seed funding, or even, it's almost like a little bit of a Series A, you think they, they, they, there maybe could and should have been a mechanism that didn't rely just on the program for sustainability, but actually said, you know, we've made a big investment in this. You know, let's, let's throw some good money after. Good. But that, again, wasn't an option for IMI or any other sponsor. So we we were left where we were.

And I was fortunate enough to be involved in some, like, like with EPA and other and other programs, cutting edge science and really learning so much about what was possible, um, in terms of our understanding of neurogenic diseases. Early detection. You know, we've got blood-based biomarkers now. We've got, you know, incredible imaging technologies, all these wonderful things happening, new therapies being developed. But that world was a million miles away from my clinic.

So when I actually went to clinic on a Tuesday afternoon in Edinburgh, um, it was almost like the clinic that I helped to set up in 1997 in Melbourne, Australia, you know, so although the science had been advancing at an incredible rate. Clinical services, were actually getting further away from the science and there's very few branches of medicine where that gap is actually widening.

I know there's always gonna be delays between science and implementation, but I was really sensing that we were actually getting worse rather than better. Maybe in COVID played a part in that. We all had the experiences of what happened to people with dementia during the, during the pandemic. So I, I thought, you know, I was. What am I now? So I was 54 years old, 53, 54 years old, and I said, you know, almost like a final roll of the dice.

Rather than trying to continue to do this through the academic and the pub public sort of sector, I thought I'll, I'll start up a company to try and bridge that translational gap. And that's what Scottish Brain sciences is. So for people inside who knew what EPAD is, I've, I've actually tried to commercialize EPAD um, but doing it through my own company. So you're not relying on multiple other stakeholders.

actually saying, you know, let's, let's bring all this in-house to try and develop the, um, the, the, the, the, the assets in some ways that we had with an epa, but doing it through a commercial vehicle.

Um, and that's the, that's the cornerstone or the foundation of, of everything we're doing in the company is, is that Iona Longitudal cohort study. And it has all the same, you know, potential outcomes that we've talked about. Um, you know, using the data, using the biobank for discovery, but also using the, the cohort study for as a readiness cohort for, for, for, for putting people into trials and our experience in Scotland.

And where we've been running this for maybe a year and a half is it works, it really does work in terms of, you know, engaging people and getting people into trials at unprecedented levels that, that we've seen historically.

Getting people to understand that, and those are the people can be the public, but can also be fellow clinicians. That this is a midlife disease that expresses satellite as a dementia syndrome. You, you needed to keep banging that drum. You need to keep getting that message out there through various channels. So the readiness cohort in, in, in, in Scottish brain sciences.

Um. Is the kind of, again, the foundation, the empirical basis for, um, Anna Borthwick who was in charge of work package six and EA now works for Scottish Brain Sciences. So that part of the company is absolutely crucial, um, to use that patient voice or the participant voice to channel that, to do engagement work, to make people realize that there is real hope and expectation that we can, you know, we can, you know, eventually cure these conditions. So I think as well as the data.

There's also, like I say, well the numbers, there's also the narrative and I think that's something we're, we're committed to also, um, developing.

I actually took consent to come into a trial. Um, and it was completely different from any other consent I'd previously done because. She'd been part of the cohort study. She'd been off to the unit. She knew my research staff, they knew her. There was this engagement. She was, she would, I mean, virtually, it was like, where do I sign?

So these trials still cost a fortune to actually run. So the, the, the, the bar to actually embarking upon a phase three clinical trial is, is incredibly high. And I think one of the things that we haven't really talked about is, but we, we kind of ran the numbers, um, on EPA and thought that, that the cost of delivering a trial to the sponsor would be quite significantly lower. Than it would've been had they just done it on their own.

Um, so I think, again, you know, the science isn't the problem. I've, I've, I've been seeing that for years. I think the problem is actually operational and, and, and, and sort of more sort of a, you know, um, practical aspects. Um, but, and that hasn't changed. And I still think there's, there's, there's still a little bit of a copy and paste in trial design today, uh, from, from trials we used to do in the 20th century.

Well. Like you've mentioned, other areas like MS and MND and cancer has, has moved on. Um, but we we're still a bit stuck.

So I think to the point you're making that, you know, when you're running clinical research, it, it, it's a shorter gap if the trial works, if the, if the drug becomes available, you are the investigator who becomes the doctor. Your research staff become the nurses and the doctors that. You know, give infusions and monitor for safety. So, so I think this ecosystem that, that, that, that we develop from a research setting leads to also be the ecosystem where, where people get treated.

So you, the, the trial participant becomes the patient hopefully quite seamlessly. And again, that's something within Scottish brain sciences we're trying to do, we're trying to deliberately blur the between clinical research and clinical practice. The pair, of course, like you say. You know, should be biting your hand off because what you're actually doing is you're much better at patient selection.

You're much better at, you know, ensuring that you have the data to hand that says, is the drug working or not working? So in like in a trial, we wanted to fail fast. You know, we wanted to kill arms. We wanted to, to look at things that were working and, and, and promote them and look at other things that weren't working. And, and, and, and maybe, like I say, make that go no go decision. The evolutionary analysis as we called it, and I think that's true in clinical practice.

You know, is this drug working for my patient? If not, let's try something else. But I think at the moment in clinical practice in the Alzheimer's space, it's kind of a one size fits all. And we don't have that, that kind of, you know, approach that, as I keep saying, other branch to medicine do, like an oncology or HIV medicine, we don't have that repertoire or that, um, or that, um, portfolio of medicines and tests to really understand what's going on. So.

If we could learn from people taking treatments, uh, outside of research, what we call traditional research.

Um, and if I can be candid, I don't think those things should have probably been designed three years before launch because I think we're not really making that seamless transition to, you know, from phase three to phase four. I mean, I think everybody knew that when these drugs with the side effects and the issues and the challenges that we face in using them because it's so difficult. Different from what we used before.

It should have been a same, a seamless phase three, phase four program that people were up at, but we, we've probably lost two or three years in terms of setting up phase four. Now, again, I'm not saying that SBS is a solution to everything, but you know, if, if we do have people who either go into a trial or go into a, onto a, onto a treatment, they stay in the IU in a cohort. So we continue to collect that data, whether they're on a trial or in a treatment.

And, you know, as long as the, you know, company survives, we should be able to develop that longitudinal data set, follow the person on their entire journey, plus or minus drug, plus or minus, you know, trial. Um, and that data will be obviously incredibly important. And then there's the real world data for people, you know, that needs to be collected as well outside of that. But I, I still think that a lot of that real world data that we have in memory clinics around the world is, isn't.

Necessarily collecting the data that we really need to understand the issue. It's a little bit, um, lacking in veracity, uh, for what we actually need.

And if you do, you know, you mitigate some of those risks. So, you know, let's not, let's not just focus on the drugs. I mean, me have, give a pal to, as you know, our good friend is, is, is, is leading in that with the finger study. So I think, you know, wrapping around the, the non-pharmacological lifestyle with the pharmacological is, is ultimately the best solution. And yes, I'm sleeping a bit better. Thank you. Are you