Alector, Inc. (ALEC) Earnings Call Transcript & Summary

Good morning. I am Shehnaaz Suliman, President and COO of Alector. We'd like to welcome everyone to the first of our thought leader series, in which we invite experts in neurodegeneration to share perspectives on their own research and clinical efforts as well as provide a perspective on Alector's research and development programs. We are hoping to host these events periodically to continue to stay current on developments in the field, especially as it relates to biomarkers and clinical outcomes. The focus of today's discussion is on FTD and AL001, our lead sortilin inhibitor program, which is developed for FTD patients with a progranulin mutation and currently in Phase III. Before we begin, a reminder that we will be making forward-looking statements that are subject to assumptions, risks and uncertainties. The agenda for today starts with an overview of immuno-neurology provided by Arnon Rosenthal, our Founder and CEO. Robert Paul, our CMO, will provide an overview of the frontotemporal dementia program, together with a reminder of the Phase II and Phase III studies that are currently ongoing. We are very pleased to have Dr. Jonathan Rohrer join us from the University College London's Dementia Research Center. He is also the Head of the Genetic FTD Initiative, or GENFI, and will be providing an overview of clinical trials in FTD as well as the importance of the GENFI cohort. We're also very pleased to be joined by Dr. Henrik Zetterberg, who joins us from -- as a professor of New York Chemistry from the University of Gothenburg. Dr. Zetterberg is a preeminent expert in biomarkers, and will be providing an overview of biomarkers in addition to neurofilament that can inform the underlying pathophysiology in FTD. Finally, Robert will provide and describe what you can expect to see from the Phase II open-label study at AAIC in July. And I'll provide some closing remarks. You are welcome to submit your questions to us through the chat function as we go along, and we hope to have a robust Q&A session. Next slide. Reminder that AAIC this year is in Denver in July, and the program for today is intended to foreshadow the data that will be presented at AAIC. We will be presenting both 6-month data, including biomarker and clinical data, as well as 12-month data from our ongoing FTD progranulin symptomatic patient cohort. And yes, you heard me correctly. We know that we've been guiding to 6 months data, but we actually will have 12 months data as available as well. And that will include both cognitive outcome assessment data and the CDR NACC FTLD as well as disease-relevant biomarkers, both plasma CSF and MRI. With that introduction, I'd like to hand this over to Arnon.

Welcome, everyone. We have over 120 people online, so I want to welcome everyone who joined us. As many of you know, Alector was created with the sole purpose of developing another broad therapeutic approach for dementia neurodegeneration. Instead of going after the misfolded protein, which was the dominated approach until then, what we undertook to do is to recruit the brain immune system to counteract multiple disease pathologies. And the scientific rationale for this approach was emerging human genetics. The human genetics surprisingly told us that a weakened immune -- brain immune system is the culprit in multiple neurodegenerative diseases, primarily Alzheimer's disease. So what we undertook to do is to harness, recruit, rejuvenate the brain immune system and target it to counteract multiple disease pathologies. As a result, all of our drugs are immune checkpoint-like molecules. They are all derived from risk gene for neurodegeneration, and they all modulate the brain immune system. Conceptually, what we do is very similar to immuno-neurology to immuno-oncology. In immuno-oncology, instead of going after the tumor directly with chemotherapy or radiation or conjugated antibodies, what happens now is that we recruit the peripheral immune system to counteract cancer. We do the exact same thing. Instead of going after a beta or tao, we recruit the brain immune system, a setup called microglia, to counteract multiple disease pathologies. And because all of our drugs are based on human genetics, we actually can develop disease signature. We have biomarkers that typify the disease that we can use as guidance effort for drug efficacy. So with this approach, in the last few years, we have identified dozens of novel targets. And by next year, we will have 7 drugs in the clinic and a robust portfolio behind that. We filed more than 300 patent applications and multiple exciting targets, and we are moving many of them to the clinic. The focus of today's meeting is our progranulin franchise. As many of you know, progranulin is a unique immune regulatory protein that appear to be involved in multiple neurodegenerative diseases. So in human, you find multiple types of genetic mutations in progranulin that cause diseases. You find people that have lost both copies of the progranulin gene, and these people develop dementia, seizure and blindness as early as the age of 13 at 100% penetrants. There is a much larger population of people that have only one bad copy of progranulin, but this is enough to invariably develop frontotemporal dementia before the age of 60. And there is a much larger population, about 30% to 40%, actually, of the human population, that have minor decrease in the level of progranulin of 10% to 20%. But this is sufficient to increase the risk of ALS, frontotemporal dementia from other causes -- other than progranulin mutation, lysosomal storage diseases, Alzheimer's disease and Parkinson's disease. So progranulin has unique genetic risk units, really on the top of the risk pyramid as it involved in practically all neurodegenerative disorders. Because loss of function or decreased level of progranulin always leads to neurodegeneration, what we undertook to do is to develop drugs that increase the level of progranulin. And we wanted a drug that increase the physiological level of progranulin, the endogenous progranulin that restore progranulin back to normal level in the right places, and that does not overshoot -- that does not increase progranulin way beyond physiological level because we know that with immune regulatory proteins, if you overshoot, you can also lead to adverse effects. And in order to develop this perfect drug, we went back to genetics to guide us. And human genetic told us exactly how we can increase the level of physiological progranulin in the body. So in human, what was found out is that low level of a single degradation receptor called sortilin is associated with higher level of progranulin. And this finding can be reproduced in rodents. If you lower the level of sortilin in rodents, you can increase the level of progranulin throughout life. And both in human and in the rodent model, the higher level of progranulin are not associated with any of the neurodegeneration or adverse effect. So we undertook to mimic the human genetic pharmacologically and develop a drug that lower the level of functional sortilin and by that, to increase the level of progranulin. So what happens in our patients, they produce less than the normal level of progranulin, but the resulting progranulin is retained in the brain 2x to 3x longer and we can compensate for decreased production by increased retention time. So we have significant ambitions with this drug. As I mentioned, progranulin is associated practically with all neurodegenerative diseases. So our approach is to start with a small very genetically stratified genetic population orphan indications like frontotemporal dementia and ALS, and then advance to the larger indications, including Alzheimer's disease, Parkinson's disease and late -- and novel neurodegenerative disease has just been identified that also is associated with reduced level of progranulin. So today's focus is going to be on progranulin mutations that lead to frontotemporal dementia. But as Shehnaaz has mentioned, in future sessions, we are going to cover other indications for our progranulin franchise as well as our other additional drugs. And I will now move the session to Robert Paul, our CMO, who will describe to you in more details where we are with our progranulin frontotemporal dementia program.

Thanks, Arnon. Good morning, good afternoon. I'm Robert Paul, I'm the Chief Medical Officer of Alector, and I will give you an overview of where we are in our clinical development program with 001. Then we come to the 2 highlights of this day, presentations by Jon Rohrer and Henrik Zetterberg, and then I will give you an overview of what you can expect to see at AAIC. Next slide, please. Frontotemporal dementia is a rapidly progressing form of dementia. There are no treatments available. Compared to other forms of dementia, it affects people that are relatively young when they're still in the prime of their life and when they're working and having families. In up to 40% of FTD cases, there is a family history present. And the main -- 3 main genetic reasons or causes for familial FTLD are mutations in the gene C9orf72, MAPT and progranulin. FTD per se is a rare disease and 20% of all cases -- of all familiar cases have a progranulin mutation. In the U.K. and U.S. combined, roughly 15,000 patients are affected, and Jon Rohrer will give you more background information on the disease in his talk later. Next slide, please. INFRONT-2 is an open-label study, and the main goal of the study was to assess safety and tolerability after chronic dosing and also to confirm that we picked the right dose for the Phase III. We need to get sustained progranulin levels throughout the dose regimen. In the Phase II, we have 3 cohorts. We have mutation carriers that have the progranulin mutation, and this includes asymptomatic and symptomatic patients, some of them brought over from the Phase Ib, and then we added 1 cohort with symptomatic C9orf mutation carriers, and this is the first time we expanded the indication. At the AAIC meeting, I will focus on results from the symptomatic FTD progranulin mutation carriers. In addition to the primary and the secondary endpoints, we also have many exploratory endpoints, including muting fluid and imaging biomarkers, and we also have clinical assessments. Based on the results, the favorable safety profile and after we had confirmation that we picked the right dose for the Phase III, we started the Phase III study last year. And next slide, please. So since July INFRONT-3 is open, and it's a randomized placebo-controlled double-blinded study. It will enroll 180 patients that have a progranulin mutation. There are 2 populations. There are patients that are at risk of getting FTD, so they have a mutation that causes -- a progranulin mutation that causes the disease. But they either have no symptoms or very subtle symptoms, but we know from their baseline neurofilament levels that they will develop symptoms in the next 2 years. And then we have the symptomatic patients that have the mutation. The primary endpoint of this study is the CDR plus NACC FTLD, and Jonathan Rohrer will give you more information about this endpoint and why we're using this. We have other secondary clinical endpoints that covers cognition and function. And then, of course, we have many, many biomarkers, including CSF and plasma blood biomarkers and volumetric MRI. And I think that's important given the reason development where it was pretty clear that having a robust data set of biomarkers can help with the negotiations with health care authorities. The study is a global study, includes 45 clinical centers across the world, and enrollment is on track. Next slide. So from the very beginning, we very closely work with the 2 major registries that are -- that exist for FTD. There is ALLFTD, formerly known as ARTFL LEFFTDS. And then there is GENFI. And GENFI is a group of research centers across Europe and Canada, that's focused on familial FTD, and it's led by Jonathan Rohrer. The aim of GENFI is to understand more about the genetics of FTD. And we were very pleased to work with them, and they provided invaluable feedback and insight that helped us to develop, to design the study and also to execute this study. And next slide, please. So now I would like to introduce you to Jonathan Rohrer. On the next slide, you'll see a brief bio. So he's senior fellow at the University College of London. He leads the Dementia Research Center. He is the lead coordinator of GENFI. He also co-leads the FTD prevention initiatives, FPI. He had written more than 250 papers, mainly on FTD. And we're very pleased that he is presenting here today. And please, Jonathan, take it from here.

Thank you very much, and I hope everyone can hear me. I -- it's always nice to give talks during these difficult times of COVID, but I unfortunately had a COVID contact this week, so I'm at home rather than in my office. So hopefully, my connection will be okay and you will be able to hear me. It's a delight to be able to talk. And I've worked in the FTD field for nearly 20 years and have spent a long time seeing families, in particular, people with genetic FTD and having spent many years seeing families, and we see people on a yearly basis, to say to people, there are no drugs and no trials. I've been doing that for a very long time. So to have got to the point where we are able to say, "Yes, there's a Phase III trial." That's really an amazing place to be in. So I'm going to talk just a bit of background about the clinical imaging side. My expertise has been really in the wider biomarker field, initially in psychology and imaging. And thanks to Henrik, who you'll hear after me, we have got involved in fluid biomarkers over the years. So FTD is complex. And I think unlike some of the forms of dementia, where if you see somebody, what you're seeing, you've got a good idea, especially if you're a specialist, what the underlying pathology is. And that's not the case really in FTD. So what you see here on the right are the different clinical syndromes we might include in the FTD spectrum, the most common form being behavioral variant FTD, but a number of language forms that fall into this group of conditions called Primary Progressive Aphasia. And then, of course, there is overlap with ALS, well-known, and also overlap with this group of Atypical Parkinsonian Disorders. Now the difficulty is when someone is sat in front of you, and the -- working at what their underlying pathology is, is tough. So if you have the condition and PSP, you've got a pretty good chance that you have underlying pathology, which is also called PSP and is it tauopathy. But for the rest of the forms, what you'll see here is the arrows that lead between the clinical syndromes and the pathology. And there's lots of connections here. It's very difficult to work out what's going on. And so we decided that working across FTD that actually around 10 years ago, we decided we would focus very much on genetic FTD, and there are lots of advantages to that. FTD, unlike other conditions, is a -- unlike other -- most of the other dementias has a high heritable component. You are also able to go here easily from left to right. And so once you know the underlying genetic cause, it's easy to work out what the underlying killer pathology is. And it allows you to study a much more homogeneous cohort. And not only that, of course, it allows a real window into what's happening in the earliest phase of the disease. By following family members who are at risk of developing the disease, you can both understand the disease before symptom onset, but of course, intervene before symptom onset as well. So that's really been very much the focus of our work for the last 10 years trying to solve this difficult into interlacing puzzle. So today, I'll just focus on progranulin. Progranulin mutations were discovered in 2006. And since that time, there've been over 170 pathogenic loss of function mutations. The majority of these are nonsense mutations and the -- although there are 170, there are probably only about 5 to 10 common ones. As you've heard, heterozygous mutations cause FTD. Homozygous mutations, which are really rare, causes odds neuronal ceroid lipofuscinosis. And that's perhaps less important clinically, but more importantly, has been extremely important to make us understand about the underlying biology of the disease. And really, the discovery of the homozygous mutations was the first step in telling us around the relationship, around particularly lysosomal pathology, but also the link between lysosomal pathology and inflammation. And also, as you've heard, the majority of missense mutations are unlikely to be pathogenic in a mendelian sense, but are generally risk factors for neurodegenerative disease. There's quite variable age at onset, which I'll talk about again in a second. And helpfully, the majority of people with this mutation tend to have behavioral variant FTD, although you can see some other of the FTLD spectrum phenotypes. And they all have the same pathology, so they all have a very specific form of TDP-43. So helpfully, a relatively homogeneous disease when we come to think about it. And of course, there are no disease-modifying therapies. I've seen families with this condition for years. Huge unmet need and no therapies for these people at present. And so FTD is poorly studied from epidemiological point of view. And I suspect any numbers that you hear or that I or others talk about are probably underrepresentations of the true numbers of people. I think it's poorly diagnosed in general and poorly diagnosed in older age groups. And that, of course, is changing with modern genetics and modern genetic testing. So progranulin -- well, certainly, FTD, in general, the prevalence, this is from a U.K. study, is around [ 11 ] (sic) [ 1 ] per 100,000. Progranulin is about 10%, perhaps a bit more percent of all FTD, which gives us a sort of rough number of working at how many people there are, at least with symptomatic carriers, and of course, there is a much larger population of presymptomatic carriers. It's a disease which is, and falls sort of somewhere in between in terms of disease duration compared to the other diseases we see. So it's not a rapid disease like ALS over -- and with a mean duration of a few years, nor is it a very slow disease like some of the other forms of FTD. So in some sense, a good model for studying FTD, neither fast and very rapid, but also not a very slow disease. So one sees measurable change over a relatively short period of time. And I think one of the things perhaps to just drive home is thinking about the fact that this is a genetic condition and this large population of presymptomatic carriers. And we see over 100 people in our presymptomatic study just at UCL. And all of those people I meet, signed at meeting a few people per week. And it's a very difficult journey. And people commonly find out that they're at risk in their 20s or 30s, some younger than that when their parents are diagnosed. And that means living for 20 or 30 years of your life with the knowledge that you are at risk of developing a neurodegenerative disorder, or for many people who've gone through testing, actually knowing that you're going to develop that risk and that you may have passed that on to your children. And I think it's a very difficult life, and people live with uncertainty and with mental health difficulties because of that. And I think the fact that there are now therapies and trials have made a huge difference to that burden and mental health burden, at least in terms of the sense of hope and being able to go into trials. And I know that's definitely the experience of the people that I have been seeing. So I think this is just important when we think about how you would enter people into trials. This is from our large Lancet Neurology paper. And from a few years, over here on the left-hand side is progranulin, and we also have data from the other genetic causes of FTD. But this is the spread of both age at symptom onset and age at death. But the important thing here is this very variable age at onset. So a majority of people are diagnosed before the age of 18, but there are a small number of people over that. It's about the same for each of the mutations. So it's not different between the different mutations. And I think the biggest real relevance for and that variable age at onset is the relationship of that individual age at onset with the both parental age at onset, which is on the left here, and the mean family age at onset on the right. So although this is strictly significant, the R value for both of these is relatively low, which means that the ability to predict your individual age at onset, either your parental age at onset or the mean family age at onset is poor. So unlike some other studies, for instance, in familial Alzheimer's disease, where DIAN and TU has used parental age at onset to stratify presymptomatic carriers, that's not possible in progranulin. So the ability to stratify presymptomatic people in a different way is needed because it can't be done by age alone in terms of predicting when people will likely develop symptoms. So a little bit about the GENFI study. And just to say, the ALLFTD study is very similar. And it's a multicenter natural history study. We've been running -- our tenth year will be coming up in January. We recruit people from the age of 18 onwards who are at risk, and also symptomatic with 30 centers across Europe. You can see in this graph, we've been slowly building over the years, up to where we are now, which is 1,200 participants. That's across all 3 genetic mutation groups who are seeing longitudinally and for some people, and we have been seeing people on 7 or 8 occasions, so a huge amount of longitudinal data. And in total, in terms of -- although there's 1,200 baseline visits, there's over 2,500 visits when we include longitudinal data. And the majority of those people have had 2 or 3, but we have a group of people who've had much longer visits, which is extremely helpful in terms of being able to model what's happening over time. And we have this very core infrastructure, which overlaps, again with that in the other cohort studies around the world, so a very structured clinical history and exam, functional questionnaires, a neuropsychology battery, MR imaging and blood sampling and also CSF. And the blood, we collect DNA for genetic testing as well as RNA, but also plasma and serum for biomarkers. So perhaps one of the most successful things we've done is really to harmonize that data collection across sites. And that was hard work if we can get all 30 centers to agree to collect data in the same way, but that's certainly been the way that we've managed to get such a good and helpful data set. So just going through a few of the key things and the key things that we think are helpful. And probably the most validated clinical measure that we use is this extension of the CDR, the clinical dementia rating scale. This is being used extensively in Alzheimer's disease. But here, there's this addition of 2 extra components. So the standard CDR, which was quite memory dominated, included orientation, judgment and problem solving and then some functional items as well. And what used to be called the FTLD CDR, but is now renamed as the CDR plus NACC FTLD, includes a behavior and a language component. And the 8 items are each scored 0, 0.5, 1, 2, 3, so a 5-point scale. And there are 2 ways then of scoring that, either as a sum of boxes, where you add up all of the scores or actually helpfully someone -- and the American groups have now developed a global score, which is useful in a different way for stratification into what we would call: 0 as being truly asymptomatic; 0.5 as being in a prodromal very mild symptomatic stage; and then 1, 2 and 3 as being properly fully symptomatic in a mild, moderate or severe way. So that definitely has the most data attached to it in terms of thinking about a clinical outcome measure. But it is a measure that you can see -- certainly, see decline over a 1-year period. And here, we see data from -- this is unpublished data from the GENFI study, hopefully just about to be accepted in the GENFI. And here, you see the change in the CDR sum of boxes and over a 12-month period in the severe, moderate and mild stage, but you also see this measurable change in the prodromal group as well, although not much change over 12 months in the asymptomatic people or, of course, in the controls. There are other measures. And perhaps the other -- the second most used and validated is the FRS or FTD rating scale, which has a pretty good correlation with an R of 0.8 and with the CDR sum of boxes and there are some differences but are pretty well correlated. And it probably subtly does measure some things a little bit different and is focused a lot more on function. There are also some other scales that we use, but these are very focused. So self-monitoring scale in the IRI, which are both really social cognition measures. And interestingly, both of them are abnormal and prodromally and actually track disease severity very well. So those are the main clinical measures. And there are also lots of good cognitive measures as well and particularly measures of executive function, which are abnormal and are abnormal from the prodromal stages. But I'm going to talk for the rest of the time mainly around structural imaging because of the real importance in the amount of work that has been in volumetric T1 imaging, which really allows you to look at both the pattern, but also the rate of change in brain atrophy. I'm going to comment a little bit about volumetric T2 MRI because there are some important findings in progranulin around white matter hyper intensity. We also collect data from other things, DTI, resting state fMRI and arterial spin labeling. And I think these are important and have a place in the future. There's lots of exploratory work looking at them. They fall to the problem and our variability and difficulties measuring across multi centers. There's lots of work, post processing work to try and solve those things. And DTI is probably the most promising out of the 3. But all of them, I think, have some promise, but it is undoubtedly much more exploratory at present. So let's talk about what you see in structural imaging. So hopefully, I can get this video to work, if not, I wonder whether someone here. And so what you can see on this video, which will replay itself over time, is somebody with a progranulin mutation. It's a coronal section, so I a cut through the brain around the ear, where you see the frontal and the temporal lobes. And on your right is the left-hand side of the brain, the left hemisphere. You can see that in the right hemisphere, very little changes over time. And this is 4 -- sorry, 3 MRI scans, which are put together into a video over time. And actually, the first 2 have been taken before symptom onset. And what you can see is this asymmetric pattern, where the left hemisphere shrinks over time, particularly around the frontal lobe, but also the temporal lobe, has increased in size of the ventricles. And it highlights the bits of the brain that really are important when we think about measuring atrophy in progranulin so the ventricle size, the frontal and temporal lobes. And here, this is from another paper looking at that change -- a very subtle change into the prodromal period and then a bigger change as we come into the symptomatic period. So T1 MRI has been used in multiple Alzheimer's trials, amazingly well harmonized across centers, lots of work being done on that. And here is looking at the pattern that we see in progranulin. It is very frontotemporal focused. So -- as will be expected from FTD, but also involves some of the subcortical areas in the striatum. And unusually for FTD, it does go back into parietal lobe as well. But nonetheless, it's very frontotemporal dominated, and that's really the burden of it. And it's disease specific, it's different than what we see in the other genetic forms. Importantly, when you look at that, and this is from the very first GENFI study, published in Lancet Neurology in 2015. When you look at it, the areas -- and this are changed, first, the insular and -- which is the region, which links the frontal and temporal lobe. And then in the temporary [ parietal ] and then the frontal lobe and the striatum, all happening before symptom onset. Areas which are all measurable change before people develop symptoms. So symptoms onset is here. These are the years before people develop symptoms. So we can measure atrophy in the years running up to symptom onset. And importantly, you can not only measure that cross-sectionally, but you didn't see that over time. And here is the annualized change in brain volume. So they change over a 12-month period. And the atrophy rates here is around 3.5% for symptomatic, and in the very early presymptomatic carriers. And here, we stratified people by 10 years pre and post likely onset. And the atrophy rate is measurable even in the late presymptomatic period. And a reminder that, that's kind of a rate of around 1.5%. It's actually what would often be seen in some other degenerative diseases. Progranulin tends to -- atrophies at a faster rate than many of the other forms of FTD. So measurable atrophy rates even prodromal. So I think structural T1 is really core to being able to measure volume loss in neurodegeneration. But just a little point on the T2 white matter hyper intensities. And this is work -- 2 studies from our group. And this is an interesting study. It's actually this person is dead. This is a cadaveric MRI scan. They were scanned within 24 hours of death, and that allowed us to register their brain to the brain slice that was taken out shortly afterwards. And it allows us then to accurately understand what you'll see these white matter hyper intensities. And what these white matter hyper intensities actually are by really going into the -- an area where we see them. And it's unusual for FTD to have white matter hyperintensities. They're relatively unique to progranulin. And the feeling is in the work. In this study, pathologically, shows very clear microglial dysfunction. It does not show vascular disease, which people sometimes wonder about whether this is, like in other forms of dementia, whether white matter hypertensives are vascular. It is not. These are areas of microglial dysfunction, and that importantly ties in, of course, to some of the fluid biomarkers that we might think about in terms of measuring inflammation in microglial dysfunction. And importantly, when you look at that over time, and there is a correlation with the amount of white matter hyperintensities and the time through the disease journey, through years and expected onset into the symptomatic period. So that's potentially something that is an important measure. So just a few last slides and to talk about the FPI. If you're interested, this is a -- this is our website. The FPI is really just a grouping together of the different genetic cohorts around the world. And as Robert said, the biggest are GENFI, which we run in Europe and Canada, and ALLFTD, which is in U.S. and Western Canada. But importantly, we also now involve groups in South America, in Australasia, both in Australia and New Zealand, but also in Asia as well. And we -- our goal has been -- really, the advent of the FPI came with the advent of trials. We started both of the cohort studies before companies were really in the field. And we recognized even before companies were in the field that one of the goals of the cohort studies was not just to try and work out what biomarkers we might use in trials, but to create a trial-ready cohort who had data that was from a natural history study that might be useful to understand trials better and to be able to quickly get people into clinical trials. And so being able to create an international database of participants has been hugely helpful. And it's allowed us really to get people who want to be into trials into the right place. We're also very keen that we can think about uniform standards and data sharing and that's really the onuses on the whole FTD community, including academic centers and industry to really meet that goal of eventually sharing data. So for us, the future is worldwide collaboration, and that means patients and families as well as academia and industry. And we have a really important group within our participant engagement board and who are very much -- all from families who've had FTD in their family for generations who are very good at being able to work with us, but also work with the industry to help guide design and have been very helpful in making us understand what it is that they want from studies and trials. And we really feel the FPI is very patient-focused and we want to be able to provide the best science and the best opportunities for the patients and families that many of us have looked after for a long time. And I will leave you with the thought that I'm now growing more over the years. And I first saw some families -- when I first started my research, maybe 20 years ago and rather sadly, there are some people who are very young and in the 20s when I first met them, and I met them because I had diagnosed their parents. And now I'm seeing some of those people really starting to develop symptoms themselves. And that's very sad, and we are very dedicated to ensuring that, that doesn't happen to the next generation of people. And we're in a much better space, and the fact that we are in a Phase III trial really is amazing, and it's not something I would have thought we would have been in 5 years ago. So I'm going to finish there, and thank a really whole group of people, the participants and the carers and family who come up year after year to be in the GENFI study. It involves a huge amount of patchwork funding to really run the GENFI study. We've never had 1 large grant to do it. And really, thanks to all of the people, and I have an amazing team of people who I work with on the study. And that team, thankfully, for the last 7 or 8 years, has included Henrik Zetterberg who really has accelerated FTD biomarker research and beyond certainly what we would have expected when we first started dipping our toes into the fluid biomarker field. It's always a delight to talk at the same meeting with Henrik. So thank you very much.

Thank you, Jon. I thought it was so interesting to listen to you and also think about this patient perspective, it's super important. So I will speak about the FTD cascade and biomarkers. Let see here how -- perhaps yes, I don't know if Rob would like to be first here.

Yes, okay, here, sorry. First, thanks, Jon, for the terrific talk. And I really -- I mean, we had a collaboration with GENFI and the other registries are really invaluable in providing us advice. Great collaboration. And now I want to introduce Henrik Zetterberg. He's the Head of Department of Psychiatry and Neurochemistry. Well, well known in the field of biomarker, not only FTD, also, of course, Alzheimer's diseases, he has published more than 1,400 papers. And we're really thrilled to have Henrik present today. So, please, Henrik, take it from here. Thank you.

Thank you very much. for that interaction and thanks for all the good work that is happening here. I will talk on the FTD biomarker cascade -- FTD disease cascade and how that can be monitored using biomarkers. Next slide, please. This is the challenge. And it's exactly like we heard in the previous talks also. We have frontotemporal dementia, we have sporadic and genetic forms. We have different pathologists in the brain tissue, and we have different genetics and clinical syndromes, which is, of course, a big, big challenge when you try to develop the exact target specific pathological processes. Next slide. The solution is to focus on a well-known pathophysiological mechanism and then zoom out. This is a common theme for this danger. This is what we are trying to do here. Next slide. So working hypothesis of the PTD progranulin disease cascade. We have a progranulin deficiency, you've heard about it before. And that leads to a number of tissue reactions and cellular reactions, which includes lysosomal dysfunction, complement activation, TDP-43 pathology and neurodegeneration. Eventually, this will lead to destruction of brain tissue and cognitive decline in development of frontotemporal variety of dementia. So this is so well studied in disease models and through genetics and through brain pathological studies. And now it has become clear that we have quite good, I think, we could say that biomarkers that reflect these different processes. Next slide, please. So we have progranulin deficiency, where you've already seen the striking results that the progranulin levels in CSF [ amount ], actually, reflect that deficiency. And this is, of course, a key biomarker in the studies we are discussing today. And then we have lysosomal dysfunction, where there are lysosomal proteins present in the CSF. And actually, to some extent, also in lab, although it's a bit hard to discern what is happening in the brain from that analysis of those proteins. [indiscernible] exosomes could potentially change that. But in CSF, we definitely know that we can monitor many of these projects. And we have complement activation with complement proteins that can be measured in both cerebrospinal fluid. And in that, again, the component proteins in the plan might not completely directly reflect what's going on in the billing since there are so many other things that happen in the current issues that might affect their complement levels and downstream. Neurodegeneration is accurately reflected by blood levels of neurofilament light. It's also definitely possible to measure in CSF, that we have done for many years. But thanks to the development in regards to analytical technology and sensitive or even ultrasensitive analytical tools like [in] [indiscernible] accounting and some other platforms that we can now measure neurofilament light with blood. We can also measure many Alzheimer-related biomarkers, which can be useful to exclude [indiscernible] the clinical outcomes with the different scales that [ Rob ] talked about. Next slide piece. Here, we have, again, the model of progranulin deficiency, where this is reflected by extracellular and bio fluid-based levels of progranulin. And just a cartoon to show that in progranulin deficiency, we have these common effects on neurons and microglia and other cell types where we can see involvement of the complement system, the lysosomal system and, ultimately, in the [ neurogenerative space ]. Next slide, please. So we start with lysosomal proteins. Next slide, please. We know for sure that progranulin mutations cause lysosomal dysfunction, and we can see it in different tissues. The retina, and we can see it in knockout mice, for example, and we can see it also in postmortem brain tissue from progranulin mutation carriers. Big changes in lysosomal structure and function. Next slide, please. Then in this paper by Huang et all in Acta Neuropathological Communications from 2020, we see that progranulin deficiency leads to increased to expression of lysosomal proteins, and they are certainly here [indiscernible] in this green squares. [ Ctsd ] and other [ statins ], and we have also [ LAMP1 ] upper regulation and these proteins are also possible to measure in [indiscernible], which is quite good to be able to translate this biomarker pipeline into the clinical trials. This is data from mouse models, programming [indiscernible] mice. Upper regulation of LAMP1, Ctsd, and other [ statins ], I will also provide some of the other proteins or genes that are [indiscernible] in this mouse model. Next slide, please. Here, we see an example of -- we see that progranulin deficiency leads to increased expression of the proteins also. So progranulin tissue in brains of progranulin patients with FTD, we see increased levels of [indiscernible], LAMP1 again -- [indiscernible] LAMP1. And we have developed a vessel to measure these proteins [indiscernible] , which will be an important biomarker readout in the studies we are discussing here. Next slide, please. Then we move to the complement proteins, next slide. And the complement system is, I think it's one of the most fascinating systems in the body almost. So complement traditional [indiscernible] were discovered by the effect on bacteria and also dying cells. But then it has been shown that regulated synaptic removal happens through a complement-related pathway. So complement proteins can tag synapses for removal. And that happens to the developing brain and it happens when we learn new things and sleep on them. But then we also have deregulated complement release, which then can result in almost a high-jacking of the synaptic removal pathway. So if we get a deregulation microglia activation, we can get disregulated complement mediated synaptic removal, which probably is one of the [indiscernible] events in progranulin mutation associated that frontotemporal dementia. So the complement proteins can tag synapses for removal. And of course, the microglia are involved in this. Next slide, please. Here, we can look at the complement gene expression pathway. So we didn't have this program in a lot of mice. This mice, and you can see this type of C1q of, different forms of C1q and how -- well, how that happens in relation to the genetic mutation. Next slide, please. This is also -- there is a very clear link between complement disregulation and the development of TDP-43 pathology, which further indicates that if one modulates progranulin function and thereby restore complement homeostasis, and could probably also diminish the effect on TDP-43 formation, which is a hallmark of this form of frontotemporal dementia. Next slide, please. Yes, we see an example of what it looks like in cerebrospinal fluid. So the complement system is expressed in cerebrospinal fluid. The levels are lower than in lab, but they are clearly measurable. It's not a difficult set of proteins to measure. So there are robust assays, so [indiscernible] in clinical trials. Here you see, on the y-axis, MMSE levels of cognitive function. And you have frontotemporal dementia patients with progranulin mutations in red squares, and then you see the controls. And you can see that the higher the complement levels, in this case, C1qa, the lower the MMSE. And you see that there is a disease-specific correlation. This correlation does not exist in healthy controls, which is interesting, but also something we should be able to [ explain ] using biomarkers. Next slide, please. Then we move to neurofilament light. We jump back one the slide, back one slide -- here we go. So sorry. And the next slide, please. I didn't figure out how to change myself. Here, you see the dynamics of neurofilament light in a disease where we have effective treatments. It's a completely different disease in question here, multiple sclerosis. That's a inflammatory disease where you actually get neuro immune attack on the myelinated axons. They are rich in neurofilament light. And when this immune attack on the myelinated occurs, the axons are injured, release neurofilament light. So here you see neurofilament light levels on the y-axis. The dashed line indicate level in healthy control -- the levels you have the controls. So if you are below -- now the [ most ] assays actually indicates that people who are in their 40s, 50s and below 15 [indiscernible] neurofilament light reasonably well stabilized and maintained. You can -- we use the [indiscernible] for [ one year ] twice a week. Here, you see the effect -- the blue line is placebo treatment and then Fingolimod treatment of these results in a [indiscernible] neurofilament light. Towards normal levels, it's not completely normal, but -- and that happens [indiscernible] in multiple doses, you often see these changes within 6 months. In the B panel here, you see Fingolimod-induced changes in the neurofilament light compared with interferon beta, which is less effective, most likely. And you can see the this type of difference between Fingolimod and Interferon. So in multiple sclerosis, neurofilament light works to take treatment effects. But we I should remember that this is in neuroimmunologic disease and the disease process is little bit -- almost not there to say it, but a little bit more simple than in frontotemporal dementia. If we move to the next slide, you see results here. The biomarker does not work that well. So we have plasma neurofilament H., and that's the heavier form of neurofilament. There were no changes in this study in an ALS treatment trial, where there were clinical data that improved. So one has to be a bit careful with the neurofilament. And one should also remember that they are slow. But I hope that this modifying against any neurodegenerative disease, eventually will result in a stabilization or even better lowering of neurofilament light [indiscernible] will happen. And we haven't seen yet in a disease -- in a neurodegenerative disease, except for spinal muscular atrophy, where the levels go down. But these are [indiscernible] in the spinal cord, and it's a treatment which is [ dramatic ], and perhaps this is not what we can expect in Alzheimer's, frontotemporal dementia and some other [indiscernible] neurodegenerative diseases. Next slide, please. Here, we see that what happens if you follow patients with the plasma and neurofilament light levels. So we have the whole FTD study that you heard about before. And in these slides, we have the [ auto stick ] optimized the old FTD population according to individuals who had higher than 13.6 [indiscernible] neurofilament light or lower, and you can see that those with higher levels, they progress faster in the disease. And this was completely replicated in the GENFI 3 cohort. So this collaboration between ALLFTD and GENFI has been a very powerful collaboration, [ expanding ] the meaning of the biomarkers and how replicable results are across cohorts [indiscernible] biomarker. But those with high levels go with the increased disease [indiscernible]. Next slide, please. And we have also the clinical rating scales that we discussed before. And as you all know, the biomarker data ideally should be linked to a clinical endpoint, at least if they are to use the [ surrogate ] markers. This was a bit challenged by the -- as you can remember a verdict earlier this week, which was [indiscernible]. Of course, the ideal situation is that we have an intervention that normalizes a biomarker and that, that normalization predicts a clinical benefit on [indiscernible]. Next slide, please. This is my thank you slide. The lower panel is the Gothenburg team, and then the upper right panel is my London team, but they are in Gothenburg on that picture. Thanks so much.

Great. Thanks, Henrik. Terrific talk. A lot of information about many different biomarkers and new biomarkers. So we're thrilled again to working with GENFI and with you. I will now give you an overview of what you can expect at the AAIC presentation. Next slide, please. So as we heard multiple times in the previous presentation, progranulin is a pivotal player in brain health by regulating lysosomal function and also innate immunity. And based on the properties of progranulin, the current working hypothesis is that progranulin deficiency leads to lysosomal dysfunction, activation of inflammation and the complement system, accumulation of TDP-43 that eventually leads to neuronal death or impairs neuronal health. And of course, this then, at the end of this cascade, leads to clinical symptoms. And based on this is hypothesis, about what we think about the disease cascade, we are measuring biomarkers, fluid and imaging biomarkers and also clinical assessments along this cascade. So we're going to start with progranulin in plasma and CSF as proof of mechanism. And as you have seen last year, we very efficiently can increase progranulin levels in the CSF and plasma and bring levels -- the decreased levels in mutation carriers back to normal. And then we look at the lysosomal properties or lysosomal function. We're measuring levels of lysosomal proteases and also membrane proteins. And as Henrik described, one of the examples are cathepsin D and LAMP, which are reported to be increased in FTD. And then the next step is to measure inflammation. For example, complement and one of the members is the C1QB protein. It's part of the C1 complex, and it's at the very beginning of the classic complement system that's part of the innate immune system. It's also important to look at complement because we heard that complement system is also involved in synaptic blooming. And then one step further, we look at how the neurons are feeling. So what is the look at neuronal health? We can do this indirectly by measuring neurofilament. And as we learned, neurofilament are parts of the structure of the neuron, specifically in axons. And if axons are damaged or stressed or dying, neurofilament are released and you can measure them in the CSF and plasma. A more direct way to measure neurodegeneration is look at the brain, and we can do this with MRI and then track tissue volume over time and measure atrophy rate as a direct measure of neurodegeneration. And then at the end of this cascade, of course, most important are the clinical outcome measures. As you know, we use the CDR plus NACC FTLD. Sum of boxes in the Phase III is our pivotal primary end point, and we have data on this also in the Phase II study. And the next slide, please. So as you know, our Phase II study is an open-label study that we can actually use historic controls to create a synthetic control. And thanks to GENFI, we actually have access to patient-level data. And based on the data we have, we were -- have been provided by GENFI, we can generate this synthetic control. So we started with all the GENFI2 subjects. We have the database with it from the data cut on -- in May 2019 that included 440 patients or participants. Some of them are actually -- or the majority almost are asymptomatic mutation carriers. And then we filtered out the FTD progranulin mutation carriers. And then we looked at the symptomatic patients and then all that had a follow-up visit so we can actually see, track or compare the cognitive decline measured by the CDR plus NACC FTLD. So at the end, we did this by a mechanism called propensity score matching method. So what we're actually looking, we tried to find patients in this GENFI database that are very similar with respect to the baseline characteristics that we had in our Phase II study. So the most important one was the clinical disease stage using the CDR plus NACC FTLD at baseline. And then we also tried to match these patients based on gender, age, the subtype of FTD. And we ended -- we identified 10 patients in GENFI registry that kind of mimics or matched with the Phase II studies. And so that's why we were able to do some sort of a pseudo-randomization so that propensity score matching mimics randomization, and we were able to come up with a synthetic control to set the context for comparison with our clinical and MRI data that you will see later this year -- sorry, later this month in July. Next slide, please. So taken together, we will present 12-month data from the symptomatic FTD progranulin mutation carriers from the Phase II. As I mentioned, the primary end point was safety and tolerability. We'll get an update on this. We'll also give an update on the progranulin levels in plasma and CSF. And then of course, the focus will be on the exploratory end points, including 12-month data from the clinical outcome, CDR-NACC-FTLD marker of lysosomal function, complement and neuronal health, including volumetric MRI, which is also an important end point. And with this, I give it back to Shehnaaz.

[Audio Gap] for those terrific overview presentations. We are happy to take your questions at this point, and I see several questions that have been queued. One of the first questions is just about how we went from -- why we are presenting both 6- and 12-month data. This is a very reasonable question. I think we've been guiding to 6-month data because we had a fair amount of uncertainty at the sites with respect to patients that would actually complete their clinical outcome assessment. Now that we have gone through the sort of COVID phase, we're pleased to say that we have 9 patients that have completed their full 12 months of assessment. And those are the patients on which you will see clinical outcome assessment data as well as the full biomarker data set. We also have biomarker data for the 6-month time point. So -- and just as a reminder, this is the symptomatic FTD progranulin cohort of patients. We will not be presenting data on the asymptomatic and C9orf cohort at this -- at AAIC. So let's move into some of the other questions that have come up, questions about -- let's start with the mechanistic rationale for -- here is a question. Progranulin loss of function underlies many neurodegenerative diseases. Can you speak to why you decided to focus on FTD first? So maybe Arnon or Robert, do you want to take that one?

Sure. I can take this. So progranulin loss of function is the most -- is basically critical for progranulin FTD mutation carriers. It means that the penetrants in FTD is practically 100%. It's close to 100%. So this is the clearest case where loss of function of progranulin leads to a disease. So we thought that, that will be a great place to start. It means that in other diseases like AD and Parkinson's disease and ALS, there are only marginal decreases in progranulin of 10% to 20% that increase risk, but they are not deterministic mutation. They don't invariably cause the disease. So we thought that it makes good sense to start with progranulin mutation that cause FTD because this is invariable. Every patient that carry progranulin mutation, one good one [ beta ] progranulin eventually develop FTD. So this was the cleanest start for a clinical trial.

Yes. And maybe I can add. So from a clinical development standpoint, as Jon mentioned, these patients are relatively young. They have less comorbidities and copathologies compared to other forms of dementia. They all have TDP-43 pathology. So they're actually a relatively homogeneous patient population. And that, of course, also helps with clinical -- the clinical design. And specifically in progranulin mutation carriers, we know that they're progressing very quickly. So that also, of course, helps in detecting treatment effects.

Just to reiterate, we are just starting with progranulin with FTD mutations. Later this year, we are going to expand already to ALS with C9orf mutations. We're already running a Phase II with C9orf mutations that lead to FTD, and we are planning with our second drug with -- that we are working on subcu formulation to go after the larger indications. So we are not neglecting any neurodegenerative disease that's impacted by progranulin. We're just starting with genetically stratified population and are expanding from there based on our learning.

Thanks, Arnon. There's a question on what is the positive end point to look like for the Phase II. Maybe I'll start with some commentary and then Robert can fill in the gaps. So the goal here is to develop a composite picture of biomarkers that track with the underlying pathophysiology of FTD. And ultimately, as Dr. Zetterberg said, the holy grail would be to correlate those with clinical outcomes. We really are tending now to focus more on a comprehensive view of both biomarkers, the CDR-NACC-FTLD as well as MRI. So in terms of what success looks like, I think really seeing the directional trend in any of those biomarkers and, at the 12-month point, any potential trends that we might see on clinical outcome or MRI would all constitute very encouraging results. So the goal again is to adopt a more composite view of a totality of the picture and define the math of biomarkers that are both proximal and distal to progranulin and pathway biology as well as clinical outcome data and MRI. Robert, I don't know if you want to share anything on that.

Yes. I mean you covered it perfectly. Just as we know that there are some proteins, like the lysosomal inflammatory biomarkers where we know they are increased in the disease compared to healthy people, so there to see kind of a trend towards normalization, of course, it would be great to see. And then that's why we created the synthetic control because -- to set basically the context for the clinical outcome and also for the MRI.

Great. And on the theme of biomarkers, actually, I'm going to ask Dr. Zetterberg and Dr. Rohrer to comment. A couple of questions about the mechanistic rationale for elevations in cathepsin and LAMP1, in particular, in FTD progranulin. Dr. Zetterberg, maybe you'd like to comment on that. And just a small -- Dr. Zetterberg, we had a little bit of trouble hearing your earlier on. So you might want to raise your mic just a little bit and speak directly into the mic. But if you wouldn't mind providing your perspective on mechanistic rationale, particularly for the cathepsin and LAMP inclusions.

Yes. We are not sure about why the levels are increased, but we know there is an upregulation of the genes. So gene expression is upregulated. But then we also have a lysosomal dysfunction where lysosome accumulate -- lysosomes accumulate. They get larger. They are sometimes also expelled from the cells. And then that will lead to increased levels. So I think we can be pretty certain that the increased levels that have been reported, if one would normalize progranulin function and that would lead to a better lysosomal -- if one again should use this big word, homeostasis, that we see a normalization. The exact mechanisms of the release are not known. That one has to get frank with -- but that's -- well, that's -- actually, the studies might tell us something here also. It will be important to [ keep this ]. But a normalization towards healthy control levels, that is what we are looking for.

Maybe I can add to this.

Sure.

Progranulin was shown to be a chaperone for lysosomal enzymes. It converts pro lysosomal enzymes to mature lysosomal enzymes. So one possibility is that in the absence of progranulin, lysosomal enzymes are not maturing and there is insufficient lysosomal enzymes, functional lysosomal enzymes. And maybe there is a compensatory mechanism to increase transcription and level of lysosomal enzymes to compensate for the decreased functionality. And again, as Dr. Zetterberg said, if we increase progranulin and lysosomal enzymes are processed properly now, there is no need for more lysosomal enzymes and then the level of the lysosomal enzymes will go back to normal.

Thank you. And maybe a follow-up question on lysosomal biomarkers. What is the supportive evidence that it correlates to cognitive function or overall efficacy? Do we have any supportive data particularly for the lysosomal markets? Maybe, Robert, do you want to comment on that?

Yes. That's an interesting question because, as you know, we are, as far as I know, one of the very early groups that actually look at the lysosomal markers. So this is definitely something enrolling. So we think -- of course, if we see normalization -- and this is a very proximal biomarker that this will then trickle down and we eventually see also the effect on the clinical outcome. However, this is something that needs to be established, and that's why we're measuring all these biomarkers also in the Phase III study.

Great. Thank you. A question about how should we be thinking about the baseline disease severity for the 9 patients that we'll be presenting data on. How much -- and a follow-up just about sort of the degree of variability that could be expected for these patients both in terms of their imaging data and clinical progression given the differences in the -- in their potential baseline disease severity. Robert, do you want to comment on that?

Yes. So yes, we have included patients with a range of the global score of the CDR between 0.5 and 2 in prodromal as well in the more moderate stage and to actually set the context. That's why we were able, by using the GENFI database, to create a synthetic control, looking for patients with very similar baseline characteristics like disease stage and age and gender. And that will set the context for the results we're going to present to AAIC.

Great. Thank you, Robert. Switching gears to talking just a little bit about the MRI. And I think Dr. Rohrer, these are really for you. A question about how reproducible the changes in T1 MRI can be expected across FTD patients.

Yes. It depends on what reproducible means. So from a perspective of cross-sectional imaging for trials, the reproducibility from day to day and week to week is very good. That's why structural MRI has been used so much in other trials. And it's a very robust -- really a very robust biomarker from that point of view. The question is how variable atrophy is -- an atrophy rate is across FTD. Well, it's very variable across the whole of FTD and -- but when you start to get into more homogeneous cohorts, it becomes more homogeneous. So when you focus down to progranulin, all progranulin symptomatic participants have a measurable atrophy rate over a 12-month period and, in fact, have a measurable atrophy over a shorter time than that. Most studies have been focused on 12 months. But when you look at some of the shorter studies, there's clear change measurable over that time. And I think like I had mentioned before, the atrophy rate is unusually -- I mean not unusually, but it is higher than, for instance, Alzheimer's disease and -- or a number of the other forms of dementia, where MRI has been used as an outcome measure over a 12-month period. So it's certainly got measurable change over 12 months. And that's measurable really in all symptomatic carriers.

Agree. And so the -- some of the questions that are coming through also have to do with really expectations, so at the 12-month point specific to our cohort. But also just to hear your general impressions, Dr. Zetterberg and Rohrer, on what you would expect to see, for example, in the MRI data at 12 months, sort of a min case and a base case. And similarly, Dr. Zetterberg, a couple of questions about just what would you expect to see going on with neurofilament at 12 months in these cohorts. So I wonder if you both care to provide your impressions and perspectives.

Would you like to start? I mean I don't...

Yes. I'd like to start. I mean -- yes, well, I mean I suppose both -- I showed data in the talk, which was essentially 12-month data from the cohort study, both in the clinical outcome, so CDR where there is very clearly a measurable change at all stages, including prodromal. And similarly, you showed data from the MRI, which is -- one expects to have lost a few percent of the brain, so during asymptomatic period, and even around 1.5% of the brain in the prodromal period. And that is when we compare that to Alzheimer's disease, where we might be looking at kind of 1% to 2% per annum change. That's a clear change over that time period. So I think, yes, partly, of course, depends on where you are at the start but clearly measurable change on both CDR and MRI over a 12-month period.

Thank you. Henrik?

And if I fill in on the fluid biomarkers, I would say that I think most of the biomarkers we have discussed, they should definitely change rather quickly. I mean the complement proteins, the lysosomal markers, I would expect that to change rapidly. But neurofilament light is a bit problematic and we know that it has a slow turnover. It is -- its half-life is 2, 3 more months, but that's also TBI and sort of cleaner conditions. So -- but I think at 12 months, I would expect normalization of the complemental lysosomal proteins and perhaps a stabilization of neurofilament light even though I wouldn't -- yes. I think I will be careful with drawing -- with predicting too much in regards to neurofilament light on the basis of what it looks like in other diseases, but a stabilization will be made.

Thank you for that. A question for us about whether we would perhaps gate additional indications from, for example, in ALS and our indication expansion strategy on what we saw in the Phase II. Perhaps specifically in relation to neurofilament but also other clinical or plasma biomarkers. And maybe I'll just start by saying it is our intention to initiate the enrollment of the Phase II in ALS, which will happen in Q3. So that's ongoing. We predicated on the strong biological rationale for TDP-43 and the C9orf repeat inclusions that we see in ALS. But perhaps Robert or Arnon, you can talk a little bit more around sort of our clinical development strategy as it relates to the FTD Phase II.

Yes. As we mentioned, we already have included the C9orf FTD patients into the Phase II. And next year, we will see data on this. And depending, of course, what we see there, we will then initiate a Phase III study. We already -- as Shehnaaz mentioned, we're going to start an ALS trial in C9orf mutation carriers. Here, as you might know, since we're not actually repairing like the C9 mutation, it's really about targeting the TDP-43 pathology. And since 95% of sporadic or ALS actually has also TDP-43 pathology, that would actually then open, of course, the gate, so to speak, for broader application in ALS. And maybe Arnon, you want also to add?

Yes. We think that there is a pretty good, both human genetic and animal model, rationale to go after ALS. So as Robert said, ALS is a TDP-43 pathology, and as Dr. Zetterberg said that progranulin may impact TDP-43 pathology to impact on the lysosome. So I think that there is a mechanistic rationale, genetically mutations, regulatory mutations that decrease progranulin by 10% to 20% accelerate the rate of progression in ALS and decrease the age of onset in ALS, particularly ALS with C9orf mutation carriers. So we think there is a sort of integrated data from human genetic and animal model showing that elevation of progranulin would be beneficial for ALS. And we think that we have enough data from our progranulin FTD to really justify expanding the indications now.

Thanks, Arnon. Another set of questions relates to the treatment paradigm and patient population, so mostly for you, Jon. Do you expect this international database now to, I guess to quote the question directly, revolutionize the way FTD is diagnosed and improve treatment outcomes?

Yes, a nice question. Of course, I would like to say that the answer to that is yes. But I think -- I suppose giving a perspective over the time that I have been working in FTD, it is -- it's been slowly progressive rather than stepwise in terms of the improvement in diagnosis of FTD, particularly outside of specialist centers, which I think is better than it was and in -- particularly, the recognition of the need for genetic screening has improved. And I think that the international collaborations have helped that and continue to help that in terms of worldwide education to dementia groups around what FTD is and the need for screening. There are multiple things that have happened at the same time, of course, including the reduction in cost of genetic panel, next-generation sequencing testing, which has allowed to diagnose more genetic FTD than we ever did. So I think bringing together consortia always accelerates research. And I hope, at some point, we can revolutionize it. And of course, I hope that improves treatment outcomes. So that, of course, is the goal and the reason for doing it. But yes, it's a slowly changing process.

Thanks, Jon. And could you comment on whether the GENFI cohort database, just the ability to use this longitudinal registry perhaps as a benchmark cohort for the conduct -- for conducting clinical trials, how should we think about that? Obviously, it's an incredible resource. And we're undergoing this exercise of defining a matched cohort to contextualize our data. But can you say a little bit more about the validity of the longitudinal registry for the conduct of clinical trials?

So I think we started doing the study with the idea that the natural history data might be useful for that kind of thing. The methodology for collection and the nature of the switch is trial-compliant, audit trails, et cetera. Those things are different than what we might have done for older observational studies. So I think from a perspective of how the data is collected, I think that is -- it's collected to a robust nature that allows it to be used for trials. It isn't quite the same, of course, of doing a clinical trial a bit less. The whole idea of collecting that data is to make it as useful as possible. And as I often say, I hope that I'm not doing an observational study in years to come. The goal is that this data is helpful and useful for trials and we are getting people into trials. So I think the rough answer to that is, of course, yes, and that's really the goal of what we're doing.

Thank you. Another overarching question about how consistent would we expect neurofilament MRI and CDR to be at 12 months. And if there are not consistent improvements, what could be some of the reasons for that? I wonder, Robert, if you want to start, and maybe Dr. Zetterberg and Rohrer can also add their perspectives.

Yes. As we mentioned, these are exploratory end points. And we know given the sample size that there are kind of limitation. I mean that's also the reason why we added this synthetic control to set the right context. But as we mentioned, for the biomarkers, like the lysosomal inflammatory biomarkers, we would like to see trend towards normalization. And again, if we see that we have a little bit numerical -- less atrophy rates or we see a trend in cognition in the right direction, I think that would be very encouraging for us.

And I could continue and just mention that from a technical standpoint, neurofilament light is a very robust marker. But it has -- there are so many reasons for why it might change. And therefore, I think the biological consistency is a bit of a challenge, and we have learned more about that recently. So I think I myself have over-appreciated the stability of this biomarker because I started to look at it in multiple sclerosis in younger populations. Now if the patients are also rather young, so I think it might work here as well. In older populations, neurofilament light is quite reliable, especially if you look at people who are 70, 75, 80. When we created our normal reference limits in my lab for neurofilament light, we had healthy people between the age of 5 and 95. And it's so clear that when you start to look at people around 65, 70, then the scatter of the results is much worse. And there are some people who take off -- even though they are -- they were in this reference sample collection, clinically healthy people, there are multiple things that bring up neurofilament light levels in people who are -- who approach 65, 70, 75. And if we look at our 90-plus people, they were not that many but their neurofilaments are all over the place. So I have gotten a little bit more careful with -- at the last year actually, in regards to interpreting neurofilament light. But from a technical standpoint, very robust, and I hope that this study will see clear changes because -- and if we see stabilization or lowering, it is a wonderful result.

Thank you, Henrik. Jon, would you care to comment on sort of the variability of MRI?

Yes. I mean I think probably I don't have a great deal to add to what I've said. I mean I think the -- in an observational study, the change is very robust. I think it is a very open question about what we might -- the level of change we might expect to see in a positive trial. I think it's -- we have a good idea of what normal change would be over 12 months. So I think anything that veers from that is positive.

And maybe just a quick follow-up. Would the MRI be expected to decline if neurofilament is stable?

And the answer to that is yes, because an MRI is -- volumetric MRI is a measure of disease severity but NfL is a measure of disease intensity. So it is -- your MRI -- if your MRI volume is changing linearly, then you may well expect your NfL to stay the same over time. It will only really change if your disease and volume is changing in a nonlinear fashion. So I think it's important to understand the difference between severity and intensity.

And over what time frame, Jon, would those changes reasonably be expected to occur?

Yes. It's a good question. I mean I think one doesn't know the answer to that because it's hard -- there's no good data to really address that with. And that's, unfortunately, partly due to the historical nature of how studies are done, which is that the majority of studies look at 12-month periods in dementia. I think what is most interesting is in some of the very early studies in progranulin, where people did early phase trials of repurposed drugs and they measured MRI over short periods, the number of at least -- well, at least one of the studies of nimodipine, you can see changes on MRI in progranulin patients as short as 8 weeks, which is very unusual for most forms of dementia. And that wasn't everyone, but it was seen in some cases. So I think it's an open question, but I think it's -- progranulin is unusual in -- that we may well see changes as an earlier time point than we might otherwise expect.

Thank you. A question about how the Phase II data will influence the ongoing Phase III, if at all. Could we see any changes to the Phase III? Maybe I'll start and say that the way we thought about the Phase II is that this is really validating data. It's open label and it's validating data for the Phase III. We've, of course, been in discussions with regulators about the design of the Phase III and have a very clear idea of what will be required for registration. The other point to add is that the design of the Phase III was actually done using a fair amount of GENFI data and modeling what we would expect to see in terms of rates of decline. And therefore, we feel quite confident about our assumptions going into the design of the Phase III, especially as it relates to CDR-NACC-FTLD, and we'll be measuring all of the biomarkers that have been discussed here today. But Robert, I don't know if you had anything else to add about how the Phase II results may or may not influence Phase III.

Yes. I think that was a great summary. Yes. We actually do not expect that this will change the design based on simulations. That's how we came up with the design with respect to sample size and also treatment duration. And we do not, so far, intend to change the design. The study is ongoing. We're on track with respect to enrollment. And we don't want to basically disturb or jeopardize the integrity by making too many interests. I think we came up with a very good trial design and we just continue.

Great. A few more mechanistic questions. Maybe these are for you, Arnon, with respect to intracellular progranulin. Is the decrease in intracellular progranulin due to the inhibition of internalization via SORT1 going to affect itself? Maybe just talk a little bit about the intra versus extracellular progranulin dynamics.

Sure. So progranulin is thought to be acting both through standard extracellular receptors and also get internalized into the cells and then act inside the lysosome. There's a wealth of published data suggesting that blocking sortilin does not impact either the extra or the intracellular activity of progranulin. Progranulin was shown to internalize and get into the lysosome in sortilin-ablated cells, and progranulin does not bind sortilin due to mutation in progranulin itself, still internalizes into the lysosome, still promotes survival of neurons indistinguishably from wild-type progranulin, progranulin that does not bind sortilin [indiscernible] lysosomal pathology in animal model, can reverse microgliosis or inflammation in microglia in animal models. As I mentioned, in human, human that are haploid-insufficient for sortilin do not show any overt neurodegeneration. So we think that progranulin can get into the lysosome through other receptors that have been identified, primarily receptor called LRP1 and another receptor called mannose-6-phosphate and that sortilin's primary function on progranulin is to negatively regulate its level of expression. And one of the many reasons we are going to use and show lysosomal enzymes is to really dispel the notion that progranulin, if you block sortilin, cannot impact lysosomal function. So we are looking forward to see how they are seen and discuss this further.

Thanks, Arnon. A few more clinical questions for you, Jon, that just relate to sort of how many patients you see on an annual basis and whether a treatment such as AL001 is more likely to be beneficial for asymptomatic or symptomatic patients or both and patients that you think would be eligible assuming success, of course. Could you comment a little bit on that and how the sort of diagnostic dynamics are changing and the patient population and then specifically how AL001 may be used in -- across the spectrum of patients?

Yes. Good question. So I suppose it depends on what and where you're talking about. In a specialist center like ours, we see probably about 150 new FTD patients per year. And we would see somewhere around 10% of people who would have a progranulin mutation. And so when we look across our GENFI centers, where we're talking about 30 centers across Europe and Canada, obviously, it multiplies up. And so I think -- I mean hard to be very more specific about that. They're obviously -- when we look at the number of specialist centers that are across Europe and America, that obviously starts to increase numbers up. And would people be more likely to do better if they're symptomatic or presymptomatic? Well, that is a golden question. And it's an empirical question, and I wish I knew the answer to that question. I mean I don't think you can -- I just don't think it's a question I've been asked many times. You just can't answer that without doing the study. I think it's just impossible to know. Of course, I think the implicit part of that question is like, everybody, we think that we would like to be treating people when there is the minimal neuronal dysfunction and neuronal loss, of course. But is that the same as saying it will work more on one than the other? That's an empirical question that we just don't know the answer to, I think.

Thank you. Yes. And this is part of the reason why we are studying both at-risk patients as well as symptomatic patients in the Phase III, precisely to get at that question. A related question perhaps on just -- which has been asked in various forms, but it's really about which of these biomarkers are most predictive and most likely to correlate with disease progression. And I guess asked another way, which of these have the strongest translatability to clinical benefits? I think again, Dr. Zetterberg and Dr. Rohrer, it would be very good to hear your perspectives on this one.

Yes. I mean maybe I start. I mean I suppose the -- it's very clear that our experience is, of course, that the change in MRI is consistent with the change, the clinical change. So the extent of -- actually, there is this very -- in the -- particularly once you get into the late prodromal period, it correlates very well with clinical severity. But there is a different question, I suppose, which I'll let Henrik answer, which is about change in these measures. And it comes back to that point around severity and intensity of whether you're showing there is -- if the natural history is that NfL doesn't change, that's not the same as saying that a change in NfL with a therapy is not showing clinical benefit. I think that those are different questions. Is that fair, Henrik?

Yes. I agree completely. So if -- my dream scenario would be that we would be able to use progranulin and lysosomal proteins to quite rapidly see that the drug is doing what it is supposed to do in terms of restoring progranulin function. And then if that eventually translates into a lowering of NfL or a stabilization, that is a very -- to me, I'm a bit NfL-biased. I have to admit because I [indiscernible]. But if that happens, then we have -- I think there is a very strong case that neurodegeneration has been modified, but talking from a [ dealing ] perspective, of course, if this could be done in blood, neurofilament can. But if it will be possible also to develop some kind of biomarker readout -- and progranulin can, of course, also. But for the lysosomal proteins, that would reflect [indiscernible] that could also be very useful to use the treatment. I think progranulin and NfL, in concert in blood, could become a clinically, extremely useful pair of biomarkers.

Great. Another one...

That depends, of course, on what the study showed.

Yes, of course. Thank you, Dr. Zetterberg. Another one for you, Jon. Help folks understand the cognitive reserve in FTD and how factors, such as the environment, education, lifestyle, may provide a reserve against the clinical manifestations of FTE -- of FTD despite the pathological burden.

Yes. There are -- it's a good question. There are relatively limited studies on that, a handful. But all of those studies show that cognitive reserve is an important, if relatively minor, factor. And so having greater cognitive reserve tends to -- is likely to have effect on age of onset and speed. But I think that effect is relatively minor from the few studies that have been done. I mean I suppose one of the key questions has always been around the reason for difference in age of onset in progranulin. And of course, that's -- which we haven't talked much about is, potentially related at least in part to a genetic modifier, which is TMEM106B, which, of course, is a key lysosomal player and binds to LAMP1 and is -- links the genetics and the clinical expression with lysosomal function through TMEM106B.

Yes. And I see Arnon nodding away. So Arnon, would you care to add some more perspective on TMEM?

Yes. Exactly. It seems as if the genetic modifiers sort of might play a stronger role in the variability in the age of onset that maybe environmental modifiers and TMEM is a great example of that. It's really -- it provides very strong protection from progranulin deficiency. And it all seem -- as Dr. Rohrer said, these all seem to be integrated in the lysosome. That's another reason why looking at lysosomal biomarkers is an important component. And that's another avenue of the disease that we are working on.

Great. A few questions on our engagement with regulators as it relates to biomarkers and whether that's something that has come up yet. And so as I alluded to earlier on, we have been in very close dialogue with FDA particularly about the design of the Phase III, which is why the design is as it is and has been sanctioned, particularly as it relates to CDR-NACC-FTLD but also the other biomarkers that are being measured. And we continue to have close discussions with them. And those will happen as we go along. A reminder that the Phase III is a single pivotal study. It's part of the reason why we do not intend to do any interim analysis in that study. It's 180 patients, and it's been powered to see a clinically meaningful change in the CDR-NACC-FTLD. And so -- and we will provide the details on the study design, outcomes and powering assumptions later this year. Robert, I don't know if you had anything else to add about our interactions with FDA and EMA.

We started actually very early. We had -- before we actually filed an IND, we had a pre-IND meeting. So we were always in very close contact not only with the FDA but other regulatory agencies. And of course, we also asked how biomarkers can contribute. At the time, they told us that there is -- so far, there are not enough data basically to support any kind of a surrogate end point. But they also said, "Well, come back once you have the data and we can have a discussion." And we're looking forward to provide the data to the agency and discuss.

Exactly. And it's a big part of the reason why we're moving toward developing a more comprehensive view of biomarkers across the spectrum of the disease. That seems to be most -- I think we've answered most, if not, all of the questions that have been asked. I wonder if I could go back to Dr. Rohrer and Dr. Zetterberg and ask you for any final or closing comments that you might have.

Henrik, do you want to start?

I'm very excited about this. I think it's fascinating that we now, in several neurodegenerative diseases, are starting to see promising manipulations of primary pathogenic pathways and that -- again, you will hear my biomarker by us, but that these pathways are possible to measure more or less directly in biofluids. I think this is -- I am very hopeful for this work, and I am looking forward to following it.

Yes. I think when we think about -- if I think about my own work, if we were doing this trial 5 years ago, we wouldn't have lots of the measures that we have now, particularly the fluid biomarkers. And just the capacity and the technology has changed hugely. But I suppose the one thing to say is really to go back to the families that I see. Just the ability to say that we have active trials is really a big change and really offers some hope where there was none before. And I think we forget that sometimes -- and I think those in the dementia field aren't necessarily within the FTD community who feel slightly jaded by the amount of Phase III trials that have been in other diseases and forget that this is really the first Phase III trial in FTD. And that really is a great place for us to be in, where I've worked in observational studies for many years. So I think that -- I feel glad to be part of this and very hopeful that this is an amazing step forward from where we were.

Thank you so much. Thank you so much for outlining the importance of GENFI as really an invaluable resource, the patients that look to us for hope. And for all of the efforts really to stimulate further collaboration to explore therapeutic options. Dr. Rohrer and Dr. Zetterberg, we're so grateful to you for providing a broad-based overview of the spectrum of biomarkers that can serve to enhance our understanding of the biology underlying FTD and, in fact, biomarkers in addition to neurofilament that are very disease-relevant and the expected changes that could be seen there. We are not moving from neurofilament in as much as we are moving toward a broader understanding of the full biomarker picture for FTD. So to our audience, we hope that you found today instructive and that we provided a sufficient preview of what to expect at AAIC. I also wanted to remind you to look out for AL003, our SIGLEC 3 program, Phase Ib data later this year; and AL101, the follow-on program, sortilin inhibitor, potential subcu formulation data, also in the second half of 2021. Here at Alector, we continue to double down on our efforts and our commitment to find treatments for patients suffering from FTD and other serious neurodegenerative diseases. And with the events of this week, I would say there's just renewed momentum in our effort, and we couldn't be more excited to continue our work. So thank you so much to our speakers and to the audience members for attending, and we very much look forward to seeing you all at AAIC in July.

Thanks.