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So I'm here today with uh Professor John Hardy. We're going to talk about the highlights from the Association for British uh neurologist today. And we're really excited to have this conversation, John. I wondered if you could maybe kick off just by giving us a short summary of your background, who you are and what you're kind of interests are and then we'll dive into the meat of A B M. Sure. Thanks for inviting me. My name is John Hardy. I'm a geneticist from Queen's Square London. I've really, well, I started actually off by doing, working on the neuropharmacology of neurodegenerative disease. But for a very long time now I've been focusing on doing genetic analysis of neurodegenerative diseases. So that's my background and it was a pleasure for me to be at the ABN and see the progress, you know, the progress in the field in general. So we're really in a, in an exciting time. Um What would you say were the kind of main takeaways from ABN? What if someone couldn't have attended? What were the main things that they should know about what happened to A BM this year? You know, the, the nasty thing people used to say to neurologists was that they were great at diagnosis but did not necessarily treat anything. And that, you know, that was close, that had enough accuracy. Uh I mean enough accuracy to be a hurtful statement. Um that is changing with respect to neuro degenerative disease. We are, it's clear moving to an era of mechanistic therapist therapies which really go to the heart of the diseases and that was really evident at ABN. The first therapy, um in this area was actually not covered. But I think it was the if you like the first swallow of the spring was the therapy for spinal muscular atrophy with the antisense therapy for spinal muscular atrophy being so successful a couple of years ago. And that was really inspired being an inspiration across the area. What was reported at A BM. Well, the disappoint, I mean, I'm going to start with a disappointment, but it was a very, very, I'm going to call it a hopeful disappointment. Uh Talk from Sarah Tabrizi on the failure of the antisense Huntingdon trial, uh in uh where they've developed an antisense. Uh, two Huntington's the, the Hunting Dumb the message. And they tested that in Huntington's disease. That trail trial failed. I think they had reasonable evidence that the reason it failed is because they were trying to higher dose too late in the disease. And it's important. I think one of the things I will say really off the top is that it's really important to see, you know, we say clinical trials failed and succeeded. I mean, it's important to say that that their experiments and if they're carefully done and well done and these trials were carefully done and well done, you get valuable data so that the next trial can build on the trial that you have just completed. And that clearly is the case with Huntington, the Huntington trial. So I'm still hopeful that the anti Huntington therapy overall will work. Sarah Tabrizi gave a great and very, I thought measured talk about where Huntingdon therapy is up to. Um, the other, um, talk which really along the same lines really was the anti Tau therapy trial given by cath memory. Um This is an anti sense to, to TAO is this going to work? Obviously knocks down the, well, not, obviously, it does knock down the tangled the towel protein. The fact that it hits the target is great news and, and this is really, it was a phase two trial. So we have to be a little bit careful in over interpreting it. But this also looked as if it was hopeful. I mean, the the biomarkers suggested that that it was actually hitting its target and reducing how in the brain of those individuals. And there was actually a little bit of data suggesting that it was reducing the number of tangles in the brain of, of, of Alzheimer's cases. So really as hopeful as one could be the papers published. I think it's in nature. I think it's in nature Medicine might be Nature Neuroscience. A couple of months ago, Cath Memory is the first author, really a really hopeful trial I reviewed. I don't want to say that my thought was the highlight. I think that the data I was reviewing which is data that I did not generate. So I I can if you like taking direct credit was looking at the anti amyloid trials in Alzheimer's disease. They've really hit the headline. Um We had a do can um ob a couple of years ago which was approved in the States but really a controversial approval. Uh There was 11 positive trial, one negative trial. And as people may know, you're really supposed to have two positive trials for approval, but it was approved nevertheless. So that was really controversial and, and the field was not settled. However, last year, there was the look on a mob trial. Uh ice I um published, they're like on a mob trial. And um what that showed clearly was about a 25% slowing of um of uh of rate of progression of Alzheimer's disease. So if you like that is the first, I'm going to say noncontroversial um proof that anti amyloid therapies work. There is a little bit of rattle people are pointing out, well, it's not rattled. The people are pointing out that you know, there are possible uh well, there are possible side effects which can be dangerous with anti amyloid antibodies. But this clearly shows that reducing and uh this trial clearly shows that reducing amyloid slows clinical progression of disease. We haven't managed to stop progression yet. It's there is still progression but it slows it by about 25%. And I think this has been really exciting. And then uh I discussed the phase two results of the Donna mapped trial in my talk. But subsequently, the phase three results of the Donnan on trial have been released as a press as a press release. So, not yet as a peer reviewed um publication and that also very similar really approach that also is um has been um uh successful with a a similar reduction in the rate of progression of disease. So, uh my view is we're turning the corner for um for these neurodegenerative diseases both with antibody treatments uh and with antisense treatments. Uh So, you know, that that's a real change. And I think the one of the things I really picked up in the meeting was a sense of optimism in general for where we are in with neurodegenerative diseases. And it reminded those Presidente present of the revolution we saw in, in mechanistic therapies for um multiple sclerosis over the last 15, 15 years, approximately where we had drugs which had marginal effect about 15 years ago. And then there was uh that caused if you like the multiple sclerosis neurologist to get organized to give these therapies. And then subsequent to that better mechanistic therapies were developed and now those are standard of care. I think we're going to follow a similar practice with neurodegenerative diseases. The first therapies are difficult to administer, require careful monitoring and have real but marginal effects. I think that though they tell us what we need to do, we, we need in the case of Alzheimer's disease to suck amyloid out of the brain. And if we do that, we, we can, we know that we now know we can achieve efficacy. So that's going to make future trials easier. Uh And hopefully we'll get better at avoiding the side effects and also maybe administering the drug earlier in the disease process where we might expect less side effects and greater clinical efficacy. So I think there's a real there was, yeah, I think there was a real feeling in my area, neurodegenerative diseases that were turning the corner. Um And uh the next five years are going to really see a change in clinical practice. It's really exciting, right? Like I think, yeah, really exciting. What you're describing is um is really hopeful. It, it's um it's beginning to turn that corner in neurodegenerative diseases for outcomes for patient's uh and really moving towards management and uh and leaning into that uh for the kind of next um the next iteration of A B and what are we, what are we hoping to see, what are the most exciting prospects that we should be looking forward to next year? What are the uh the key trials that are ongoing now that we should begin to see some reports coming out for uh next year's ABN? I think the big area, the big area for progress now has to be, I think biomarkers of these diseases. That's where I mean, well, let's go back to the clinical trials themselves in all of these trials. The Donnan A mob trial is going to be um presented in a formal way in a couple of months in at the Alzheimer meeting in Amsterdam. So we'll see the data, the real data in all the trials. I've been mentioning we're going to see open label extension trials and and those open label extensions are going to be important as well. Are we going to see the control and the cases and controls diverging further? Are we going to see better effects? Those are things we are going to see and that data is on the way. So it will be the next ABM for sure. I think in terms of progress, what we really need to do is get better at diagnosing the disease accurately and early and in this regard, by fluid biomarkers are going to be uh everybody believes fluid biomicroscope are going to be key. You know, a lot of of these trials are often organized around pet scans. Pet scans are really not available generally well in the UK, but more generally outside of the US. So we need high through high throughput way of diagnosing accurately early and fluid biomarkers are the way we think we can do that. So I'm expect the next A BM to be full of fluid biomarker type analysis. Um I should say that here in the UK, the Alzheimer's Society and A R U K have just announced within the last week, a 4.5 million lb grant specifically who um get bio marker aided diagnosis into the general clinic, not just in the specialist centers but into the general clinic. So we're just at the beginning of the, of this organizational shift going from specialist centers having high rates of diagnosis to more general better diagnosis uh across general clinics. And that's going to be very, very important and that will help with earlier diagnosis to start earlier treatment. Right. Yes, exactly. I should say that what we were, everybody believes the reason for the side effects uh which is called Aria in the with the anti Amyloid therapist is that the first thing the antibody hits is the blood vessels in the brain and they're stuffed full of amyloid uh by the time the treatment is given. So you get an inflammation of the blood vessels. So if you can diagnose earlier, you might catch, you should catch the disease earlier and that might on its own, have a better outcome, but you might also to some extent avoid the side effects of the antibody hitting the blood vessel amyloid. So you've got a double hit if you can get better at diagnosing very early. And what does that look like in terms of timeline? So, if I am not going to be able to do a biomarker diagnostic test in the general clinic, as opposed to the specialist neurology clinic, what does that mean in terms of time of diagnosis? Are we shifting time of diagnosis by six months, a year? Two years earlier? What is that like? Uh I'm not really sure, I would say four or five years if we can get four or five years earlier in, in terms of diagnosis, there's an enormous amount of work. The trouble is that this type of work of its nature is not, cannot be speeded up. I mean of its nature, you know, you're waiting to see if you make the diagnosis early where you right? And there's no way of, unfortunately, the experiments quite simple but of its nature, it takes several years. So, well, that's just the way it is. You can't speed, you can't speed those sorts of things up. Sure. Uh Professor Hardy, what a wonderful snapshot summary of, of ABN. So we've moved from diagnosis into treatment and now looking forward to a BM 2020 for how do we even bring that diagnosis? Two uh earlier time point so that we can yet again improve, improve treatment. Thank you so much for your time today and really great to get your insights and, and snap short summary for those who you couldn't make it. We really appreciate your time. No, thanks for inviting me. It's always a pleasure to explain how things are moving along.