ALS/MND Platform Trials Update Webinar

Welcome to today's webinar from the International Alliance of ALS associations on an update on the ALS, MND platform trials. For this webinar, we have English and Spanish captions available. If you're joining us live on zoom, please check the chat box as we are adding the instructions right now, or scan the QR code on screen if you have another device available. And if you're watching the recording in our YouTube channel, you will find the instructions in the video description on how to activate

the subtitles. But as the Seminario web tenemos subtitulos en inglés y espanol disponibles, si se unen a nosotros en vivo via zoom en la casilla del chat. Ya estamos agregando las instrucciones en este moment o pueden acceder a las traducciones por medio del codigo QR en pantalla usando otro dispositivo y si estan viendo la grabacion en nuestro canal de YouTube, encontraran las instrucciones en la descripcion del video sobre Como activar Los subtitulos. For this webinar, we are using automated

captions. Please bear in mind that this kind of translation is not perfect and many variables can affect accuracy and errors are possible. However, if even if a few words are incorrect, you should still be able to get the meaning in context. Thank you to our sponsor, Mitsubishi Tanabe Pharma, without whom this webinar series would not be possible. For those of you who don't know me, I am Jessica Mae, Programs Coordinator of the International Alliance, and I am joined today by an incredible panel

of experts who will be who will provide you with an update on the ALS, MND platform trials moderating. Today we have Doctor Nicholas Cole, head of Research for the MND Association in the UK. Doctor Cole completed his PhD in Saint Andrew's University in Scotland in the UK, before research postdocs in Saint Andrew's, Dundee and Sydney, Australia. Doctor Cole started his own lab in the University of Sydney, modeling ALS and NDI in zebrafish before establishing the MND Research Center at McGuire Un

iversity in Sydney. Doctor Cole returned to the UK with his family and dog Vegemite to take up his position as head of Research at the MND Association. In 2018. Doctor Cole is a keen kitesurfer and the Guinness World Record holder after his kite, The Reef MND fundraiser in 2015. Joining him in the panel, we have doctor Sabrina Paganoni, MD, PhD, and an associate professor of PMR at Harvard Medical School, Spaulding Rehabilitation Hospital. She's also the co-director of the Neurological Research

Institute of the Massachusetts General Hospital and physician scientist at the Healey and AMG center for ALS. Her research focuses on clinical trials and therapy developments for ALS. She is the co-pi of the Healey ALS Platform Trial. Her research has been funded by the NIH, nonprofits, and industry, and she published more than 140 peer reviewed manuscripts and received several awards for her work, including the 2021 top ten Clinical Research Achievement Award. Joining Doctor Paganoni in the pan

el, we have Doctor Ruben van Eijk. He is MD and biostatistician, appointed as Assistant Professor at the University Medical Center in Utrecht in the Netherlands. He obtained his PhD in neurology biostatistics, entitled Optimizing the Design and Conduct of Clinical Trials for ALS. His current research focuses on new statistical models to combine survival and longitudinal longitudinal data, integration of real world evidence into drug development, as well as developing new endpoints that addresses

the multidimensional nature of ALS and differences in patient preference, and completing the panel we have Doctor Suvankar Pal. He is professor of Neurodegenerative Degenerative Disorders and Clinical Trials and consultant neurologist at the University of Edinburgh. He is co-lead investigator of the UK wide innovative Multi-arm multi-stage MND Smart trial, the Scottish Motor Neuron Disease Register Care, MND and Deputy Director at the and Rolling Clinic, co-investigator of the UK Dementia Resea

rch Institute and an honorary professor at the MRC Clinical Trials Unit at UCL. Now some final instructions. Any questions you have for our panel? Please write them in the Q&A box. I also want to take this opportunity to thank everyone who submitted their questions. There is a lot to cover and we will do our best to answer as many questions as we can in the time we have. I will now turn it over to Doctor Cole, our moderator for today. Thank you Jessica, and thank you, everybody, for joining us.

in this webinar, wherever you are in the world and whatever time of day you're joining us, it's a great pleasure to be able to host this webinar and address some of the questions. to our excellent panelists. So without further ado, if we could begin with your presentation, please, Sabrina, thank you. Thank you very much for inviting me. It's a pleasure to be here. Let me share my screen. So today I'm going to be talking about the Healey ALS platform trial. It's a pleasure for me to work with Doc

tor Mary Sukovic, the Pi of the trial. And I serve as the co-pi. And this trial is something that's really, a passion for us. and most of all, it's a great opportunity to work with the entire ALS community. The trial is grounded in robust academia, industry, partnership, and the reason you see many logos on this slide is because we have several academic medical centers, industry partners and partners in the community, including several foundations and patient advocacy groups. support the trial.

The trial is sponsored by the Healey Center at for ALS and Mass General. And the reason we came together with all the people listed on this slide is because we know that there is a great need to accelerate the development of new drugs for people living with ALS. and we do, appreciate the fact that now we have such a great, engaged, patient community, not only in the US but around the world. and today's webinar is actually an example of the wonderful collaboration with different patient groups an

d different patient advocacy organizations like the International Alliance. and really, everyone wants to come together and think about different ways and complementary ways to accelerate drug development. So it's a pleasure to be here today. I'll present our experience. So I'm happy that I'm going to be followed by other experiences. and there's different ways of, of running platform trials, but they're all complementary. And I think we can learn a lot from, from one another. we know that there

are hundreds of companies now in the ALS space, and several investigational drugs that are waiting to be tested. And that's why we we that's why we thought this is the right time for a platform trial. I'm sure my colleagues will agree. this is a time where we have more trials for ALS, MND than we ever had before, and this is the time to accelerate the drug development, because we have so many drugs in the pipeline. So in a nutshell, why are we doing platform trials? Well, platform trials aim to

meet the needs of the ALS community. And we did some simulations with our statisticians and we figured out that by running the these different trials as part of of a platform trial, we would have several advantages over traditional trials. First, first of all, we're going to, reduce reduce the number of people who are assigned to placebo. We're cutting the time it takes to develop new drugs, and we're making more efficient use of resources, time, money, patient effort, and overall effort from t

he community. And ultimately, what we want to achieve is to rapidly move drugs that are more likely to succeed to phase three. So our trial is a phase 2/3 trial where we're really trying to screen drugs rapidly. and I will explain how we're going to we do it. We have several endpoints, including biomarkers. And and ultimately we want to move drugs rapidly to the next phase in their drug development process. In order to do so. when we decided to launch the trial in 2019, we partnered with the ent

ire ALS community in the US to launch the trial efficiently and efficiently. And so we got a lot of input from industry, from the FDA, from patients, and foundations, and also from ALS scientists, experts, sites and investigators. And so we designed the trial. That would be a win for all stakeholders. So we started in 2020. and essentially the first thing we did was to build our common house or our infrastructure that we are using to test multiple drugs. As I said earlier, there are many drugs i

n development, and if we were just to test them one at a time, each using its own house, its own processes, its own approach, it would take much longer to get to the first effective treatment and also, if we were to run trials as standalone trials only, it would be harder to learn from the experience of each trial. And so here we we did something completely different. We kind of, dismantled the way we do trials normally, and we built a new house with strong foundations. And the strong foundation

is our common protocol or master protocol, which allows us to gain operational and scientific efficiencies. So essentially we have a common house where we can host many regimens. And when we say regimen, we mean a different drug with its own matching placebo. And because we use the same protocol, the same infrastructure, we can, first of all, start up regimens or drug trials faster. And also we can share the learnings and use a common placebo group to reduce the number of people assigned to pla

cebo. And so we started in 2020 with three regimens, three different drugs. I'm just naming them, A, B and C here. and then 2021 we added regimen D in 2022 we added regimen E. And then in 2023 last year we added regimen F and G. So overall we're using the same protocol again in phase 2 to 3 protocol. We're using one central IRB or ethics committee. That's, you know, the committee that oversees the safety and the welfare of the participants. We are one central governance structure, which means th

at we are, essentially doing all the data management, project management outcomes, training, all the quality controls are centralized so that we are sure that there is, continued refinement of the process and very high quality data because we continue to train the same group of investigators, the same group of, of staff at the different sites so that we can continue to leverage and continue to grow as a as an infrastructure, as a platform. So far, we have included several regimens which means, s

even drugs with matching placebo. and we have been enrolling in the US at over 70 enrolling sites. And so far we have included, over 1300 participants. So this is a large scale trial and we continue to grow. We are currently in discussion with, four different companies. and, hopefully we'll add more regimens soon. So each regimen though is, the same in principle. So we have essentially an 18 month program where the first six months are placebo controlled. And the the second half, or I should say

the last part, the last 12 months are active treatment extension. And so we test safety and efficacy of the drug in the placebo controlled period. That's six months. when we compare each drug to placebo to the shared placebo group. And then we can also collect long terme safety and long terme survival data by following participants during the active treatment extension. So if you think of this as a block, it's essentially an 18 month block where the first six months are placebo controlled and t

he last 12 months are active. Treatment extension. And the goal here, as I said earlier, is to provide go, no, go decisions to inform the clinical development program of each regimen study drug. So it doesn't really matter what drug it is. But you know, the kind of the structure or the concept and the approach is the same. I will say that the drugs are selected by a group of ALS experts. So we have a dedicated ALS therapy evaluation committee that continues to meet, on a regular basis to evaluat

e the drugs that are in the pipeline. And we have several conversations with industry. And when they're ready, we consider them for, inclusion into the trial. So we collect a number of endpoints, number of outcomes, in the placebo control period, the primary outcome is the change from baseline in disease severity as measured by the Alsfrs-r, score, which is a functional measure and survival over 24 weeks. And we also collect a number of safety secondary and exploratory endpoints that are relevan

t to ALS, including respiratory function, muscle strength, survival, a number of biomarkers we measure Neurofilament levels in all participants, and we also have specific biomarkers depending on the drug. Now I want to, go back to the to the fact that it's very important for us as an academic group to continue to learn about ALS and continue to advance science. So, testing drugs is is obviously the primary goal of the trial, but it's not the only one. What we want to do is to leverage the trial

and the unique and ever growing data in sample repository of this trial, as a unique opportunity to advance science. So we are we are testing DNA in all participants. Neural filaments in everyone. A number of biomarkers with thousands right now really thousands of, biosamples that, are collected and stored and lots of extra bio samples that will be available for sharing. And we also use a number of digital outcomes such as speech analysis and home spirometry. And we continue to add additional ou

tcomes. For example, the roads patient reported outcome was added for the current regimens and we are considering more outcomes or samples to be added for future. for future regimens. And all of this is an opportunity to continue to test new endpoints, new scales, new biomarkers as they become available. Because obviously this is a very dynamic and evolving field. And so we want to be able to continue to adapt, which is another feature of the platform trial and the platform approach in general.

You can continue to adapt the trial and learn from the trial to continue to to get better and also inform not only our trial but the field in general. So so far, again, we have, designed this, this study, to be a perpetual adaptive trial. We wanted to be able to provide decisive answers and direction with efficient execution. And so that's what we have done since 2020. we know that some of the drugs tested, the drugs are listed here, actually had negative outcomes. and so the programs were stopp

ed. And that's actually, you know, meeting the goal of the trial, which is to provide efficient direction, is a subsequent phase three trial worth it? And we know that it was not for some of the drugs to other drugs. cnm-au8. And Pridopidine are moving forward to phase three testing and, regimens F and G, which are a drug, developed by calico, AbbVie, and a drug developed by Denali are currently enrolling participants. We're getting very, very close to completion of enrollment. And so we will ha

ve the results over the next few months. Another goal of our trial is to continue to share our experience. So, for those of you who are listening and may be interested in learning more, we are publishing our papers as open access papers for the entire community to see them. So our first two papers, were published in Annuals of Neurology. You can follow the links and the QR codes to read the full, paper and supplementary material. we have several other papers that have been submitted for publicat

ion and hopefully will be available over the next few months. So to conclude, the Healey ALS platform trial is essentially a multi-stakeholder partnership that has the goal of accelerating ALS drug development platform trials are becoming popular not only in neurology or ALS, MND, but also in the neurosciences. We are actually in discussion with several other groups. We met with almost 20 groups from different fields of medicine, because people want to learn from our experience and develop their

own platform trials, because we understand that platform trials are faster, they make more efficient use of resources, and they can serve as a biomarker endpoint development engine. As I said earlier in addition to testing drugs, we can also advance ALS science. As the trial that I described the Healey ALS platform trial is an adaptive perpetual trial. and an initial learnings from the trial, including go no go decisions for the first five regimens, which were the primary goal of the trial. But

we also continue to learn about novel biomarkers and endpoints that have been collected. And we plan to share data and samples with the scientific community as they become available. For those of you who want to continue to follow our progress in real time, with our patient navigation team, Kathryn Small and Allison Bullat, we have a direct central resource for people living with ALS. And it doesn't matter where you are located, you can always call us or email us. and the QR codes here, I want

to highlight that we do weekly webinars, which are free and available to the public, where you can ask live QA questions. for, for our, trial. And we have the ALS link, which is a newsletter, for our information and, and we have had really, fantastic opportunity to connect with the, ALS community worldwide, via these webinars. And, and somebody sent us a quote recently told us, you know, Healey to me just screams collaboration and being smart about the data. And I want to thank the person who se

nt that comment, because that's exactly what we wanted to achieve. Collaboration and being, smart and efficient with the data so that we can make progress faster. We could not be doing this without the help of the entire ALS community. So I want to thank the participants in this trial. and really, we could not be making progress without research partners like our patient population. So thank you for the opportunity to present our progress. Please continue to follow us and join us at the weekly w

ebinars or email me anytime. Thank you very much. Thank you. Doctor Paganoni. just to add, we can put the links to those, webinars in the chat hopefully. And also, they are recorded and available on YouTube. So if anybody wants to catch up on those regular updates, they are available. Thank you very much indeed. So we're now going to hear about the magnet trial. from Ruben van Eijk. So without further ado, over to you, Ruben. Thank you. All right. Thank you. let me see. All right. I hope it look

s okay. So, yeah, I will give a brief update about the magnet platform. So, it continues about like a webinar that we gave before, and I think it was September, 20, 22. So, so one and a half year ago, so the original idea of the, of the magnet study was, was to continue like, like Sabrina said, at, at the phase three, so that that we focus really at the, at the end of the drug development stage. So where we try to provide definite evidence if, if the drug is, is doing, having some benefit. So in

terms of benefit to survival in our case, so the design, was a large international study. So it's running across Europe and also in, in Australia. so it's a randomized study. So the idea was to have like multiple different drugs where patients then would be randomized to, so we would start initially with three compounds. And the design was quite different from from other phase three studies, I think. And the main difference was the, the way how we select patients. So it's based on a prediction

model. so that allows more patients to be included, so less restrictive, so broader populations. we also changed the way how we follow up patients. So not every patient is followed up the same duration. but it really depends on how much information we have and how much information we need. So so we try to minimize the exposure to placebo, but also the time that the patient is spending in the trial. So only, continuous trial as long as necessary until we have like a definite answer, whether the t

reatment was beneficial, benefiting, and the, the, the third, major innovation, I think was the, the genotype stratification. So that's something that we still don't do very often in trials. And what we try to do in this platform study was to, determine beforehand the genotype of the patient and then allocate the patients to, to the drugs, that were most likely to, to benefit, those patients. So how it looks like in a schematic, this was the original idea. So it looks complex, but it's quite, qu

ite straightforward, actually. so we have three different compounds. Initially we had so we had the lithium, we had the triumeq and we had the TX 001, which later become the the oral edaravone from, from Ferrer. at the beginning of of the study, patients are being genotyped. And then depending on the genes that they have, they will be allocated or randomized to a specific treatment. So if a patient wouldn't have a certain HCC genotype and, they would be positive for some, some HLA gene, then the

y could only be randomized to placebo or to like the, TB double W001. In this case. so this was the original idea, but but like I said already in September 2022, is that there were all kinds of developments back then that that complicated, like the, the, the conduct of of two of the arms. so, so one arm was was difficult in, getting the funding for, for the platform study. So in the end, it was decided to, to run that one as a standalone study. and the other arm was taken over by a company. And

that company then also decided to run a standalone study. So in the end, the magnet platform study was actually run with with a single arm. so the study was still submitted, as a platform study. So, it's also also currently, being registered as a platform study. So in theory, we can still, add new arms to it. but as I will show later, is that the trials where we're moving is slightly different, different direction. but the trial is, is, active, and it's enrolling in multiple European countries a

nd also in New Zealand and in Australia. so a little bit about the update of the lithium arm of, of the magnet study. so the lithium arm, we only enroll patients who have a certain genotype. So that's the insert in a, genome type. and what we built for this platform study was mostly to see, how can we efficiently get to know the genotype of, of a patient? Because that's something that wasn't being determined, at the diagnosis. So it's not part of the, of the standard diagnostic workup that we do

for patients. So that was the main challenge that, that we encountered. So how can we, get the genotype? how do we actually know if a patient is carrying the gene and that across multiple countries, across multiple continents? So, we build a new central infrastructure for that. So all the sites in the world, they send, the DNA material to, to one location. And then based on that location, that one central location then determines whether the patient is eligible for the study. but what we notice

is that there was also a lot of variability, across centers. So we have like one site in Sweden, in which we noticed that, that the prevalence basically is nonexistent. So, I think of the 30 or 40 patients that were screened, only two of the patients have the gene while, based on population based, studies in the past, we would expect at about 15 to 20% of the patients carry the genotype. So, this has been, causing a lot of, complicating factors, for the rollout of the study. so, so here below,

you can then see, like, the, the actual enrollment rate, of, of the study. So it's the cumulative number of patients that are in the study and, you can see that it's a very slow process. So these are like really challenging, aspects not so much to the platform study itself. but I think, to, to do, genome, genetic studies in ALS. so, so what, what we're, considering now, so based on our experiences, actually, that we know that that there's some need for flexibility. So, that, oh. Oh. Excuse me. S

orry. Is the screen still showing? Yeah. Yeah. Sorry. so, so that there's some need for for flexibility. So. So we noticed that there was, for some of the, compounds. There was a need, that they wanted to have, like a standalone study. So. So where are we going towards now is more like a hybrid, solution. So where, we try to develop, like, a core protocol. So a standard protocol for, for the clinical trial. So that's similar as to what Sabrina, explained. so where we standardize all of the outco

mes that we're going to collect, also like the design aspects. So how many patients will be enrolled, how long the study will be. and based on that standardized protocol, then try to define a common infrastructure. so that's, that's really about like how the way, how we collect like the genotypes, but also like the operational aspects of which sites are, are included or which hospitals are included. how do we do the drug distribution? so that's all outlined in like one, common infrastructure. So

that's the house that was Sabrina was also mentioning about. But that the individual studies, that we're doing, remain separate from each other so that we have some kind of a flexibility in the way how we do, how we do studies in general. so, so what we're thinking of is to create, like this, standardized protocol, not only for phase three studies, but then actually for the entire, drug pathway, so that we develop, like a standardized protocol for the first stage, of drug development. So the ph

ase one studies and try to, to build then the story all the way till phase three. so it's, it's not in a sense like a platform study, in which multiple studies participate in under the same, study protocol, really. But it's, it becomes more like of a, of a network of, of trials, in a sense. so, yeah, in the end, what we try to achieve is something like a hybrid solution. So between having a platform study, which really is like one study in which patients are randomized to multiple compounds, or

having still, two separate studies which follow exactly the same protocol, the same kind of, operational aspects, but in which the studies are still separate so the patient can still choose whether he participated in the first study or in the second study. but we by by still using the same protocol, you can, somehow allow for some kind of flexibility. So so that's what I try to explain here on, on this slide is if we have, for example, three different time periods. So we start with with one stud

y. So that study is just being randomized in patients 2 to 1. So about two thirds get active and a one third get placebo. but if there then comes a second study and, the sponsors of that study want to participate together. then we have the flexibility to, to, try to combine those two studies together. So, in a sense, then you can lower the placebo allocation rate for both studies because they can can borrow it in that sense. so what we what we try to do, and that's something that we're still wor

king on, is to build this level of flexibility into more like a hybrid, platform study. so the, the main take home message, I think, of, of this update is that the, original, so, so the original mechanistic platform, is still ongoing. it's ongoing with, with one arm, and, what we noticed mainly is, that it's in some scenarios, it's difficult to do, a platform study, in multiple in multiple countries. So we're leaning now more towards like a platform of trials rather than to a platform, study its

elf. so where we still have, like the individual studies themselves, but somehow they, they need to follow one overall trial protocol. And, and infrastructure. So with this, I would like to, to finish and thank you for your attention. Thank you. Ruben. And if anyone has any questions, please feel free to put them in the question and answer box as we go along, and we'll try and deal with them at the end. That's, very interesting information. Thank you. And I'll hand over to Doctor Van Keppel, who

's going to tell us about the MND smart trial. Thank you. Perfect. Well, thank you very much for the invitation to speak today. it's exciting to be back a couple of years after we first introduced the concept of MND smart. And to follow the two great speakers that we've heard this morning, I hope it's a complementary session. So MND Smart is very much an interdisciplinary community of people working in the United Kingdom based around drug discovery, state of the art models for identifying drugs

to take through to definitive phase three trials. innovative trial methodologies. So state of the art statistics and thinking about how we can design multi-arm multi-stage trials with adaptation and crucially, also people living with the condition. We've designed everything in partnership with people living with MND/ ALS, and our interdisciplinary team now extends across over 100 people in our over 23 sites in the UK. And you can see here some pictures of of individuals that are gathering in thi

s. In the summer of last year, clinicians, research nurses farm assists people who do the basic stem cell biology. And really all of these people are committed to improving outcomes for people living with MND/ALS. So we launched MND Smart back in February 2020, and it was just before the Covid pandemic broke. And we've continued to recruit at pace, 15 to 30 participants a month. And we've now opened at 23 sites across the country from the very north of Scotland to the south coast of England and

across all four UK nations. We've randomized over 750 participants, and during this time we have conclusively evaluated two interventions. And as Sabrina mentioned in the opening talk, there are many efficiencies of the Multi-arm multi stage platform. And these two interventions have been tested in half the time. That would have been taken in a comparable two arm traditional placebo randomized controlled trial and really what we're striving to do is to increase equity of access for people living

with MND throughout the UK, irrespective of where they live, what their social status is or their ethnicity. So this schematic outlines progress with MND. Smart. Since the launch in February 2020, we've chosen to launch with repurposed medicines that have a good evidence base for efficacy in in motor neuron disease. We started with interventions memantine and trazodone. Our primary outcome measure is survival. This is a definitive phase three trial, but we have interim outcomes that look at cha

nge in ALS, FRS. So the primary interim outcome measure is ALS, FRS and then we look at all of the accumulating data as it's being collected in a dynamic way at interim analysis points. And in October 2023, we had a definitive stop for memantine and trazodone. And this was after over 100 people in each of those treatment arms had been followed up for over 12 months, and we looked at the ALS, FRS change in addition to survival and functioning, we're also looking at a number of other outcomes that

are important to people living with MND. ALS, like the impact of drugs on cognition, on mood, on quality of life, and also we heard about the role of biomarkers. We're looking at neurofilament light chain, but a whole host of exploratory biomarkers as well. We launched our third intervention in April 2023. And one of the efficiencies of the Multi-arm multi-stage platform is that we at that point had a number of sites already up and running in the UK and managed to launch this simultaneously acr

oss those sites and started gathering data at pace across those sites. And our first interim analysis for amantadine will be this August. Now, I mentioned that everything we do has been in close partnership with people living with MND. Really our patient advisory group has been at the heart of study, design and delivery. Of course, they remind us all of the time that there's nothing worse than living with MND and the plan to introduce new drugs for testing in the MND smart platform really opens

up an avenue of hope. And together with our patient advisory group, we've introduced a number of innovations. We've tried to decentralize the trial to make sure that it's accessible to as many people as possible, and that we can follow people up through their disease trajectory, even into more advanced stages of illness. And this has been achieved by couriering medicines to people's homes, video conferencing based follow ups and more recently, also innovations like remote consenting of people, r

emote electronic diary cards and remote secondary outcome measures. So how do we select the drugs that we've been testing? Well, I mentioned that we have a large interdisciplinary team, and this includes a number of leaders in the field for drug discovery. And it really is a new era of drug discovery where we can screen thousands of drugs at pace using stem cell based models, looking at pathological features of motor neuron disease in a dish. So looking at how the misfolded protein TDP 43 aggreg

ates and how drugs affect that, how motor neuron excitotoxicity is affected, but also how the drugs act on supporting cells like the astrocytes and the microglia in the brain. And there are some emerging animal models that are very exciting as well. And using these screening approaches, we've identified further targets for testing definitively in MND. Smart, including a class of drugs called calcineurin inhibitors and Jak STAT inhibitors. And our plan is very much to introduce tacrolimus as a ca

lcineurin inhibitor for definitive testing this summer. And baricitinib is the next drug after that. And we feel that combination therapies may show promise. And that's something we're planning downstream as well. And we heard that these large platform trials also support infrastructure in gathering valuable bio resourcing information and we have, like the Healy Study, a large bioresource now of well characterized samples extending over 18 months. And we're working together with colleagues in th

e UK Dementia Research Institute and internationally to develop new biomarkers and also to identify better ways of targeting targets for drugs, to identify whether they're working or not. We're also very interested in speech as a noninvasive biomarker, and we're leading a digital pathfinder project that's looking on acoustic signals for early detection and monitoring of people with motor neuron disease. And so far, we've banked several hundred voices from a range of neurological disorders, inclu

ding motor neuron disease. And we hope to incorporate this as a secondary outcome measure in the trial soon. And these sorts of trials have a huge demand on infrastructure data integrity following people up for many years and of course require investment. And we work very closely with a number of grant awarding partners in the United Kingdom. And we're very grateful for their close support through the study. Since 2020 and ongoing investment into 2028 at least. So the next steps for MND smart, a

s I mentioned, are introducing our new treatment arms intervention for would be tacrolimus later this year, then baricitinib, then a hope for combination therapies. And we've already established infrastructure and a platform that's ready for pharma testing as well. So in summary we've developed a platform and infrastructure across the UK that has allowed definitive testing of separate interventions. shortly after launching less than four years. It's highly efficient, as we heard before, in terms

of time, participant resource, financial resource. And we've managed to secure rapid recruitment despite the Covid pandemic. And fewer than 10% of people with MND. ALS had taken part in clinical trials and MND prior to this, and now a large majority of people have an opportunity to do so because of the infrastructure we've created. The pre-specified interim analysis guides early successful stopping, and it's much more efficient than continuing for long periods. And close work with people living

with the condition has enabled high rates of recruitment, retention and completion of outcome measures. So I'll stop there and thank our patient group and colleagues across the UK that have supported us in the last few years. Thanks very much. Thank you very much indeed. And thank you to all of our speakers. And, if you'd like to come back on to the camera, we can ask a few questions. We have a few that have come in from the chat. I'd just like to start perhaps with, I mean, it's important to,

to emphasize that the principle of the platform trial is to really be able to speed up, trials and trial design. So I wonder if Doctor Paganoni you might touch on that. And if you have any kind of idea about how much it might speed up the time to get a drug into a trial compared to a standalone trial, if you could comment on that. Yes. Yeah, that's a great question. And obviously, that's for the other speakers as well. They touched on this, that, you know, the fact that we now have and others ha

ve an established infrastructure nature means that startup times are reduced because sites are already up and running. There is a central governance structure, and therefore, there's very robust processes in terms of data collection, on site activation, training outcomes, training and biosample processing. So really the the only kind of, time when you have to put a little bit more work into a platform trial, is it the very beginning? and that's great. And now we're past that. We also, like our c

olleagues in the UK, launched, around the time of the pandemic. So, I hear you, you know, it was a time to really push through a lot of challenges. But now that we are over that bump, essentially the infrastructure is up and running. It's it's ready. It's pharma ready. As you said, it's, it's available to accommodate new interventions. So that's, you know, the first advantage is operational. the other advantage, I would say, because we, we're able to share a placebo group. and so you essentially

reduce the number that you need or people that you need per drug. And that also creates efficiencies in terms of, being able to achieve more with fewer participants, which also reduces cost and accelerates the timelines. So there's a lot of ways in which, you know, one can accelerate drug development. I love the point that was just made about interim analysis. We also did stop one arm at an interim analysis for futility. And that's one feature of this adaptive trials where you can actually get

answers, faster. So there's so many ways in which a platform trial, I mean, I think we could all go on and on and explain why I think this is really the way to go in the future. That's why there's so much interest in neuroscience. Thank you. Yes. we can touch on the on the learnings from negative, outcomes in a moment, but, Doctor Powell would you like to add add to that about the ability to speed up and to select which drugs can go into the platform? yes. So I think that was a fantastic summary

of the efficiencies. I think if you think about a traditional two arm study design with placebo and active treatment arm, by the time you've identified the drug, got some funding, got the regulatory approvals done, the site training, set things up, gathered the data, cleaned the data, reported on the data. That's a minimum of five years, a minimum of five years for that intervention. And by testing all of these drugs simultaneously against a contemporary, contemporaneous control, we're getting

definitive results much sooner, much more quickly. And as Sabrina was mentioning, there are so many drugs now that are worthy of definitive testing. And so these platforms allow us efficiently to test them at the same time rather than in in sequence. And so that's one of the real advantages. And we're also looking at pooling placebo data because there are efficiencies in that as well. We think it is important to retain a placebo arm. I know that there are other ideas about whether it should be a

n open label study, that everyone should have access to an intervention. I think in a randomized controlled trial, there still is an important role for placebo, not least safety concerns about interventions. but minimizing the number of people on a placebo arm obviously has big efficiencies. Thank you. Yes. And, Ruben, would you like to comment on that and perhaps, tell us about the the attractiveness of a trial to, companies, versus academic trials as well. Perhaps you could touch on. Yeah, yea

h, yeah. No. So I completely agree. I think there's, there are many efficiency gains. I think the efficiency gain is, is mostly the operational aspect. So like as Sabrina pointed out, that that you build up this house and you keep that house and then you can keep running doing the trials there, because building up that house, that is usually what takes like one half year or two years, in order to start. So I think that that's the main efficiency of, of a platform study. there of course, there's

efficiency in borrowing patients, but I think and borrowing placebo patients across trials. But I think in relative terms that that is probably less efficient than, than having like this central, infrastructure. But yeah, what I and what we noticed that recalls is that there is both from, from the academic perspective, but also from an industry perspective. There are some, some desire for some level of flexibility in the study design and, that in a platform study, sometimes that is not possible

because everything is already fixed. in the protocol. So yeah, that's why we encountered quite some trouble with two of the three arms. in the end, decided to go down to a separate study, because of all kinds of issues, because the platform was too rigid, for them to participate. So that that was a very unfortunate. And, also with the the new trials that we're thinking of and like also the new companies, we noticed that there's a lot of, appetite for like a flexible standalone study rather than

like a platform study. So, so that's, that's why we try to find like a middle ground, but yeah, we're not entirely sure yet how that middle ground should look like. But, Yeah, yeah. Thank you. And, you mentioned the prediction model. So the principle with, Magna as well as MND Smart is that, you can get more people in the criteria, is less rigid for getting more people into the trials. so there is a question about PMA and Pls, whether people with PMA and Pls would be acceptable into into magnet,

and we can cover that as well for, Healy as well as smart. Do you want to comment on that please Ruben. Yeah. So so for PMA patients under the new criteria for ALS, they would qualify because they fold in under the Gold Coast ALS. And that usually includes like the PMA patients as well. So, if they have like if they fulfill like the Gold Coast, they less criteria and they and they meet like the, eligibility criteria set by the prediction model, then in general, they are eligible. pls remains a

bit of a separate group. and I think even if we would extend like the Gold Coast criteria also to them to include them, I think many of those patients are, are very, very slowly progressive. so, so they probably wouldn't meet like the criteria that, that we set for the prediction model at the moment. Yeah. Thank you. And Suvankar, could you want to touch on, inclusion criteria for MND smart. Yeah. So very much driven by our patient group. We've gone for broad inclusion criteria. on the basis tha

t we want generalizable results to the whole population. So if we're, it can be the lumpers and splitters here and say that these are all subtypes of different diseases or they're all on a spectrum. And if we do find efficacy that it will be extrapolated then relevant to everyone living with these conditions. We've obviously had to factor in. If people do have a slow rate of progression, then the interim analysis, measure may not be as good. So we don't look at Alzheimer's change in slow progres

ses. but we do look at overall survival, which is a hard outcome in those individuals. And it gives them an opportunity to participate in trials and contribute to all the other, aspects like bio resourcing as well. So we've gone for a broader inclusion criteria. We we take part in a number of studies that use the TRICALS criteria. and I can understand the reason for trying to get a, a quicker answer, but it does lead to disappointment when those individuals at either end of the spectrum are excl

uded. thank you. And, doctor Paganoni, would you, like to tell us about the selection criteria? There's a question in the chat. Sorry to. Absolutely. What are the what are the key steps in an ALS MND patient, would typically go through in considering participation in joining a clinical trial? Perhaps you could tell us about how that happens in the HEALEY trial. Yeah. So the first step is contacting a site that's participating. and, you know, these trials tend to enroll in many centers, in partic

ular for the platform trial, we enroll at over 70 centers in the US and as I said earlier, there is a patient navigator in case people are not connected already with any of these centers, we can help make the connection. And then the first step again is, is in, going through a screening process. And I want to go back to the previous topic of sort of, you know, with eligible for these trials. And so, trials eligibility criteria are determined by a number of factors. One is obviously safety. We do

n't want to enroll. You know, we cannot enroll people for whom the particular intervention could be dangerous, maybe based on their own comorbidities or other medical problems that they may have. But importantly, from a statistical and scientific point of view. so the primary goals, the primary goal of these studies is to be able to detect a treatment effect. And so, people that, progress very slowly, for example, as was just mentioned, may not contribute to that because they are, you know, they

they don't change over the trial period, which is actually good. from a clinical perspective, but can affect the results of a trial. So I do want to mention that in our case, for people who are not eligible for the platform itself, again, due to either safety or other baseline characteristics, there is an evolving and growing concept of expanded access or compassionate use, which is separate from the trial itself, and it's meant to address the needs of people living with ALS who may not be elig

ible for trials for a variety of reasons, but are still interested in contributing to research and having access to an investigational product. So that's a kind of a parallel or companion path that was established. because of patient advocacy in the US, specifically, I'm sure it's available elsewhere. I can only speak to what you know. I'm familiar with, but essentially, there is a law in the US that allows for federal funding for this parallel study. So I just want to mention that for people wh

o may not be eligible for the trial. Thank you. And in terms of, collaborate across across each other's trials, you know, there are obviously differences between each platform trial. I just wondered if you could each touch on really how how you might share information or what you've learned from each other. just to educate our audience about the collaborative nature of MND/ ALS research, perhaps we could start with, you, Ruben. Thank you. Yeah. So sorry, I was just answering the, the other quest

ion in the chat, but about the collaboration process. Yeah, I think that would be, that would be excellent because. Yeah, as I mentioned, like, I see, like the platform trials are building up, building on each other. So, like, the answers that we get from HEALEY, they are probably very valuable for, like the study in this, the smart MND study or, like, our own, magnet platform. So I think there is indeed, like, room for collaboration or at least see how we can align like the platform so that the

answer that you get from one platform can be used in the, in the design or like somehow, in the conduct of, of the other study and collection of samples and the idea of developing biomarkers, that's presumably you're looking at similar biomarkers. And you mentioned biomarkers specific to the drugs that are being tested. is there a sharing of that information across the community? yeah. So we do we do collect biomarker. But I think that that's not in, there's not no active collaboration yet at t

he moment like across our platform. So I think there will be an excellent, opportunity to, to set something up. we we do like, like, as Sabrina mentioned. And, also try to validate, like, novel outcomes such as the roads or maybe like, speech, modalities or, or other outcomes. So, but to make that. Yeah, I think yeah, it could be an important objective to see if we can make that data available to everyone. Yeah. Something like Proact or something. Yeah, yeah. that's how I would like to comment.

Yeah. No, I've learned a lot today from listening to the others speak. So I think, you raise a good point. And I think people who are participating in these trials would have an expectation that there's some sharing of information, whether it be around learning about the infrastructure and the delivery and the protocols in these trials or biological samples that come from them. There are obviously international collaborations that are established already. But I think you're right that these, the

re's a unique approach that we're all taking here and there's learning, learning that could be shared for sure. Yeah. Sabrina. Yes. I mean, I have to say I'm very excited about the opportunity to collaborate. I think we all had to put in a lot of work around the pandemic to build the house. But now that the house has been built, there's so much more that we can do. I also want to mention that as long as you know the placebo data is used for active trials, it's a little bit harder to share data a

nd samples simply because the trial is still active. But I think we are all getting to the point where the first few arms were concluded and so now, as all these arms are published, and, you know, hopefully this year, then we will be able to to really start sharing the data and the samples. It's our intention, in fact, to donate samples and data to public repositories. and the only reason we haven't been able to do so yet is simply because we were still using those samples and data for, for acti

ve, testing. But now we are getting to the next stage, I think. So I will say that the next few years, will be very exciting in terms of the learnings that we can get from all these collaborative efforts. Yeah. Thank you. And then just to touch on what we have learned from the from the arms that have stopped, first of all, how how is that the fact that the arms are stopped, communicated to the people that have given their time and energy, etc. to take part in the trials, which is really importan

t. Clearly. And then what have we learned about pathways? You know, can we can we write off one pathway because one particular drug has not shown efficacy or can you just expand on what we've learned from from those, non positive outcomes? doctor Paganoni, if you could start. Yeah. So in terms of communication, as I mentioned earlier, we have weekly patient webinars in general for our trial. Those started in October 2020 and have been ongoing. So we continue to update the community both on enrol

lment rates. what's happening in the trial and results? I will say that specifically for every person that actually participated in the trial, before we issue a public press release and a public announcement, we always organize a conference, a kind of a closed conference for the participating sites. And the actual patients, the participants, everyone is invited so that they learn about the results first. And then we also follow up with obviously public announcements as well as the webinars where

, you know, we invited companies, scientists, etc. to kind of dive deeper into the results. and, and now we are actually in the process of publishing everything which will be available, open access. So people can actually see the results. That's great. So important to to share that openly. Suvankar, would you like to comment on your MND smart two arms similarly. So we work very closely with our patient advisory group. And actually the news about the arms not continuing was something that was pre

sented by our patient group through videos that we shared on social media platforms, and also with our charity funders who helped disseminate them. in terms of communication with the sites that work very efficiently. what we're going through now is the actual data cleaning so that we could then have the definitive final results, then unblinded the participants that wish to be unblinded and similar approach to Sabrina. All of this, all of this will be published in open access journals so that eve

rything will be available freely. Thank you very much. Well, we're nearing the top of the hour, so any questions that we haven't got to, we will endeavor to answer, offline and get those answers to people. And I'd like to thank our three speakers today. And also, as we've all echoed, really to thank every person, families and their carers affected by MND and ALS, of which none of this research and none of none of these trials could take place. So it's a huge, commitment from people. And we reall

y, really appreciate that. So thank you very much to our speakers. And I'm going to hand back now to Jessica who's going to close the webinar. Thank you very much. Thank you. On behalf of the Alliance, I want to say thank you to our panelists. it was such an important topic and so information and everything you do is, absolutely fantastic for all of us in the ALS community. So thank you very much. I also want to take this opportunity to thank you again, our sponsor, Mitsubishi Tanabe Pharma, who

make this webinar series possible. And a big thank you to our audience for joining us today. And I wish you all a great morning, afternoon or evening, depending on where you are in the world. Thank you. Thank you. Thank you.