Welcome to Athira Pharma's webinar lead-up to the LIFT-AD readout: Understanding the Primary Endpoint and Continued Need for Effective New Treatments in Alzheimer's Disease. As a reminder, all participants are in listen-only mode. Following prepared remarks, there will be a Q&A with analysts. A replay of today's webcast will be available on the Investor section of Athira's website. I would now like to turn the call over to Mark Litton, President and CEO of Athira Pharma.
Thank you, Alyssa, and good morning, everyone. I am Mark Litton, President and Chief Executive Officer of Athira Pharma. On behalf of the Athira team, I thank you for joining us today for our discussion focused on the lead-up to the LIFT-AD readout and understanding the primary endpoint and continued need for effective treatments in Alzheimer's disease. Before we begin, as noted on the following disclaimer slide, I'd like to point out that throughout the course of today's program, we may be making forward-looking statements, and please refer to our company filings with the SEC concerning our risk factors that could affect the company. At Athira, our mission is to transform the treatment of neurodegenerative diseases by halting their progression, thus enabling and inspiring patients to resume their normal lives.
Today's webinar will feature the innovative work being done at Athira to treat neurodegenerative diseases, starting with Alzheimer's disease, along with discussions with two key opinion leaders. We are delighted to be joined today by Dr. Suzanne Hendrix, a leading researcher and statistician, and the founder and president of Pentara, a boutique CRO specializing in statistics and data management in neurodegenerative diseases. Under her leadership, Pentara has supported the study design, data collection, and analysis of greater than 100 clinical trials since 2008. Dr. Hendrix has more than 30 years of clinical trials experience with time spent at CROs and pharmaceutical companies, including projects across many disease areas. She has been instrumental in the analysis and reporting for multiple regulatory submissions, including NDAs, PLAs, and ISS and ISC documents.
She has extensive experience in optimally measuring progression over time and identifying outcomes that are likely to be sensitive to the effects due to treatments that modify important aspects of the disease. In addition, we have the pleasure of being joined by Anton Porsteinsson, a world-leading neurologist and director of the University of Rochester's Alzheimer's Disease Care, Research and Education Program, or AD-CARE. Dr. Porsteinsson has devoted his career to the care and study of individuals with memory disorders. He participates in the University of Rochester's Memory Care Program, and he is internationally recognized for his clinical research and considered one of the leading experts in Alzheimer's disease and dementia. His interests lie in biomarkers, imaging, and novel pharmacologic agents in the treatment of Alzheimer's disease and other dementias, both in terms of cognitive loss and behavioral disturbances.
He is a leading investigator for many prominent national Alzheimer's prevention and treatment trials and has conducted major clinical trials with cognitive enhancers and core stabilizing agents in dementia, as well as psychotropics for behavioral changes associated with dementia. I would also like to mention that Dr. Hendrix is a consultant to Athira, and Dr. Porsteinsson is a member of our scientific advisory group. Please note that any opinions expressed by Dr. Hendrix and Dr. Porsteinsson are their own and do not necessarily reflect the opinions of Athira Pharma.
As we fast approach what we expect will be an exciting data readout from our Phase II/III LIFT-AD study of fosgonimeton in mild to moderate Alzheimer's patients, we thought this would be an excellent opportunity to take a closer look at the importance of the primary endpoint of the clinical trial, which is Global Statistical Test, or GST, and its meaningful role as a measure of cognition and function. It is also an ideal opportunity to review the therapeutic landscape and the patient journey from the perspective of a leading neurologist who treats these patients every day. We are advancing our efforts in neurodegeneration, specifically in mild to moderate Alzheimer's disease, because it is a massive and poorly served market where current treatments have limited therapeutic benefit on cognition and function, two key measures of disease that have the most meaningful impact on patients' lives.
So, with that brief overview, let me turn the call over to our physician experts. After each of their brief presentations, Dr. Javier San Martin, Athira's chief medical officer, will have a Q&A session with both Dr. Hendrix and Dr. Porsteinsson. Following that, we will call the open for your questions. With that, let me introduce our moderator for today's event, Dr. Javier San Martin. Javier joined Athira's team this past April, and he brings more than 25 years of drug development experience with a proven track record leading cross-functional project teams to drive global development and commercialization strategies for multiple drugs across large and rare diseases. Throughout his career, Javier has guided therapies from proof of concept through regulatory approval, with special emphasis on aligning late-stage development efforts with viable commercialization paths.
Javier's experience has given him a wealth of knowledge of clinical and drug development, which I'm sure will make today's discussion engaging and dynamic. With that, I will turn the program over to Dr. San Martin. Javier?
Well, thank you so much, Mark, for that kind introduction. Good morning, everyone. Pleasure to be here. I'm really excited to join in the Athira team at such a relevant moment where we are about a few months away from uncovering a very relevant study, the LIFT-AD, that hopefully will enable a registration program. Nice to meet you, and I look forward to many more interactions with you guys. Next slide. Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of the amyloid beta and the phosphorylated tau pathology. As a consequence, it triggers a cascade of events driven by inflammation, mitochondrial dysfunction, oxidative stress, excessive astrocytosis, and synaptic dysfunction.
All these lead to neuronal damage, neuronal death, loss of network connectivity, brain atrophy, and as a consequence, loss of memory, impairing cognition, and then eventually, and ultimately, loss of independence and function, which is what impacts not only patients but family and the society as a whole. So, hepatocyte growth factor, or HGF, is a neurotrophic factor that promotes neuronal health, repair, and function, and it's been known for many, many years. Fosgonimeton is potentially the first-in-class small-molecule drug candidate that is able to cross the blood-brain barrier and positively modulate the HGF/MET signaling pathway or system. So, in the end, the mechanical function of fosgonimeton is through this system, which is known to reduce inflammation, promote regeneration, provide neuroprotection, and hopefully modify the course of the disease and the underlying conditions. So, these are typically described as the neurotrophic factor.
In the next slide, I wanted to share with you some of the work that's been done at Athira over the last number of years. They use the preclinical model of mice challenged with the exogenous amyloid beta. This is a very well-established model to replicate the typical features of pathological features seen in Alzheimer's disease. These bar figures have three bars. The gray one represents a sham control. The red represents the animals where the AB was injected and replicates, as I said, the feature of Alzheimer's disease. The blue line represents what happened when these animals are treated with fosgonimeton. As you can see, we see positive effects in inflammation, where we clearly see the effect in the non-treated animals, and it's mitigated for the most part with fosgonimeton.
You can see the increase in protein pathology in the untreated animals that is also diminished by the treatment with fosgonimeton. The same is true with regard to the neuroprotective effect, measured as the hippocampal neuron survival. Again, it really reversed the process. The neurotrophic effect, as I said, by synapses in the hippocampus, is also restored. And finally, a function behavior type of test called Y-maze, it also restores function, really not different from the sham control animals. So, all these together really represent what we expect to see in the human brain that hopefully eventually translates into clinical benefit. So, let me now switch over to the clinical program. The first study I want to mention is the ACT-AD study. This study was completed, and it was an exploratory phase II study in which we enrolled 77 patients.
The key inclusion criteria in the upper left of this slide show that we include patients 55-85 years old with a Mini-Mental State Examination of 14-24 and a CDR Global Score of 1 or 2. They had a clinical diagnosis of dementia and Alzheimer's disease and could receive prior cholinesterase inhibitor. And of course, as many of these studies, the patient and their physician and caregiver should be reliable, able to come back to the visit and have an expected lifespan beyond the 6 months. So, patients were randomized to three treatment groups: 40 milligrams of Fosgo, 70 or placebo. In this study, the primary endpoint which was not met was the iADRS, and then, of course, safety and tolerability. There were key important secondary endpoints such as the ADAS-Cog11, the ADCS Clinical Global Impression of Change, and the ADL-23.
We also assessed some biomarkers of relevance. There were a number of key learnings in this study, namely that fosgonimeton was well tolerated with a favorable safety profile. There was, however, an unexpected potential pharmacodynamic interaction with the acetylcholinesterase inhibitor, and that is relevant because I'll show you data that has to do with the effect in the subpopulation that did not receive cholinesterase inhibitors. Also, importantly, about 85% of patients in both ACT-AD study and also the ongoing LIFT-AD study transitioned over to the open-label extension. Right now, we have a large group of patients that have been treated with fosgonimeton for a long period of time. Of course, this population will be very useful to understand the long-term safety of fosgonimeton in this population.
In the next slide, I wanted to share some of the clinical endpoints and the results from the ACT-AD study. On the left-hand side of this slide, you show the result from the ADAS-Cog11, and this is in the subgroup of patients who were not treated with cholinesterase inhibitor, about 8 to 6 through the duration of this observation in the placebo group, and approximately 17 patients on fosgonimeton 40 milligrams. So, you can see that there is an improvement of 3 points in the Cog11 compared with placebo. And during these six months, the cognition was maintained for the most part in patients treated, considering that these are patients with more severe disease, mild and moderate. On the right-hand side, we have the panel of four very relevant and novel biomarkers. The two tops have to do with protein pathology. The first one is the A beta 42/40.
As expected in the placebo group, there is a decrease, which means worsening, and that is prevented in the group that was treated with fosgonimeton. P-tau also, again, as expected, and as the disease progressed, you see an increase in P-tau with no changes in the case of the fosgonimeton-treated subjects. Then NfL, which is a biomarker that is getting more and more interest in this field of neurodegenerative conditions. Again, as expected, patients progressed. There is more neurodegeneration expressed with these increases in NfL that is completely mitigated by fosgonimeton treatment. And finally, and importantly, inflammation assessed by GFAP, which is a very specific CNS-related inflammatory cytokine and marker. And again, we see an increase in the placebo group and a decrease of this inflammation biomarker in the fosgonimeton-treated group. So, with that, let me go over the LIFT study design.
I want to first start by clarifying the changes that we did in this study as the study progressed and as we were learning more and more. Initially, in this study, we also allowed patients cholinesterase inhibitors, and they were randomized to three treatment groups: 70, 40, and placebo, very similar to the ACT-AD study. Now, in September 2022, we decided to exclude the patients on background therapy with cholinesterase inhibitor after understanding the data from the ACT-AD trial and had the suspicion on this pharmacological interaction. Then, later in May 2023, once we saw that the group 70 milligrams had more frequency of injection site reaction and that impacted tolerability and adherence, we decided to change the study and only continue to enroll patients to either fosgonimeton 40 milligrams or placebo. In LIFT, we enrolled a total of 554 patients.
They all will be part of the safety database. 315 patients of that group were actually in the fosgonimeton 40 milligrams or placebo without concomitant use of cholinesterase inhibitors. This study duration during the double-blind phase is 26 weeks, and then the patients roll over onto the open label extension for 48 months. As we move forward, we've been amending that protocol to allow patients to continue on treatment. The primary endpoint of this study is the global statistical test or GST, and Dr. Hendrix will talk a lot more about this. But this is an approach that uses composite endpoints of the two key psychometric measurements: the ADAS-Cog11 assessing cognition and the ADL-23 assessing function. Of course, the key primary endpoint, or another primary endpoint, is safety. We have a number of secondary endpoints, including the individual scales, so Cog11 and ADL-23.
The neurodegenerative biomarker plasma NfL is also a secondary endpoint. Then we have, of course, a number of other secondary and exploratory endpoints to learn from. Next, I wanted to make a couple of comments about the interim analysis that was conducted with the intention to optimize this study design. The approach the team took was to really use the adaptive methodology in study designs to have an interim analysis done by an unblinded independent DMC to reassess the sample size, so have a new estimation of the sample size. This was done when the first 100 patients not on concomitant cholinesterase inhibitor completed 26 weeks double-blind phase of the trial. With that data, they conducted Monte Carlo simulation to estimate what the sample size should be necessary to achieve significance using the GST as a primary endpoint.
There were very specific rules, as it is the case with adaptive study design, to call the study for futility or to continue the study with a maximum number of patients enrolled that was, again, predefined that will enable or allow for statistical significance, assuming this model works well. So now, let me make a few comments about the important endpoints of these studies. Again, Dr. Hendrix will describe in more detail the approach to the GST, and also she will put the clinical context to it. But I wanted to make a couple of comments about the ADAS-Cog11 psychometric test, which is the gold standard to assess cognition in patients with dementia. It has 11 tasks, both patient-completed and also observation by the assessment. It measures three components: memory, language, and praxis, which reflect the process by which cognition directs motor action.
So the ADAS-Cog11 is well suited for this specific population of patients with mild and moderate AD. The other component of the GST is the ADL-23 and includes 23 items. This is done with the caregiver. Again, very well-validated scale. Both of them are considered by the FDA and other regulatory agencies at the appropriate endpoints that will show improvement in function and feeling and survival eventually. So with that, I would like to hand this over to
Dr. Hendrix. She will expand more about the endpoints and the clinical relevance. Suzanne. Thank you so much. I'm Suzanne Hendrix from Pentara Corporation. I'm happy to be here to present combining evidence across multiple endpoints with global statistical tests. So what is a global statistical test?
It's a type of composite outcome that assesses the treatment effect across multiple aspects of disease at the same time, and it's particularly relevant for disease-modifying therapies. Now, what I want to do is remind you that lecanemab and donanemab studies in phase II both included composite scores. Lecanemab used the ADCOMS, which was a combination of cognitive scales and the CDR sum of boxes items, which is a global scale. And their composite in the phase II showed significance with a p-value 0.034. But the CDR sum of boxes in that same scale did not show significance, even though this was the regulatory endpoint that they would end up using in their phase III and ended up being highly statistically significant in their phase III, as shown on the second row here. Now, donanemab, also the donanemab phase II study, also used a composite scale.
In this case, it was the iADRS, which is a combination of the ADAS-Cog and the instrumental activities of daily living from the ADL scale. It's actually very similar to the GST that's being used for the Fosgo study. The p-value for the combination score for the composite was 0.04 and statistically significant in the phase II. The regulatory endpoint, CDR sum of boxes, had a p-value of 0.57. This doesn't mean that there isn't a treatment effect on the CDR sum of boxes. It just means that it's highly variable. When you're in a phase II study with sample sizes that are not as large as you'll be able to have in phase III, these outcomes are highly variable and can have big jumps from one person to the next. This additional variability makes it very hard to see statistical significance.
This was still in favor of active. It was still in the right direction, but it was not statistically significant. In the phase III, both the composite, the iADRS, and the CDR sum of boxes showed high statistical significance, as did all of the other outcomes. What this demonstrates is that when you have a phase II study, it really makes a lot of sense to use a global test or a composite score. The reason for that is you get additional stability by combining across endpoints. That additional stability gives you better prediction of what really will happen in your phase III study. Then when you have the larger sample size of a phase III study, you can get significance on all of the endpoints, including the regulatory accepted endpoints for approval. For fosgonimeton, the GST is combining cognition and the ADL scales.
So it's very similar to these composites that were used here. And it makes sense in phase II to use something more reliable, more robust, less variable, and then have that predict what will happen in phase III. So on the next slide, what we show is symptomatic effects. Symptomatic effects are temporary. And what that means is that when you take the treatment, you see an immediate effect due to treatment. And when you come off of the treatment, you lose that treatment effect, and you drop right back to where you would have been otherwise. So we represent these with vertical lines showing that your points are pushed up while you're on a symptomatic treatment. And as soon as the treatment is gone, you go right back to the regular progression rate shown with blue in the placebo arm.
On the next slide, we show the global statistical test. The global statistical test used in the fosgonimeton study is a combination of the ADL scale and the ADAS-COG scale. The ADAS-COG is a patient performance measure primarily. That's important because it shows how well the individual can actually perform cognitive tasks in the clinic. The ADL scale is an interview with the caregiver reflecting over the last four weeks of their life and indicating whether or not they're able to perform daily tasks. Another component that could be included would be something like a global clinical rating. All of these are indicators of whether there is a true treatment effect. For this study, the ADL and the cognition gives us the patient and the caregiver perspective on whether or not there's a treatment effect. It is actually a performance metric and then a report.
Next slide. Disease-modifying effects are permanent benefit. We think that what's happening is you're slowing down the actual process that's building up biologically with the disease. What that means is that instead of progressing at the normal placebo rate, as shown with the bottom blue line here, you would progress at a slower rate. We show horizontal arrows because we're essentially pushing the same score later in disease because the disease is now accumulating more slowly. You are then a later stage later in the study. You would achieve that same stage of disease. What that means is that we're really slowing down the buildup of the disease. When you come off of treatment, as shown on the right here, you would go back to your same rate of progression, but you would never lose the benefit that you achieved while the disease progressed more slowly.
That slower accumulation of disease stays with you forever. And what that also means is that the type of patient you look like when you're on drug is exactly the type of patient you really are, so that when treatment is removed, you just progress as a natural person from that point onward. Next slide. Showing these side by side, symptomatic effects are temporary and give you an immediate boost to your points. Disease-modifying benefits are permanent and give you a permanent slowing of disease that you accumulate while on treatment and then keep even if you come off of treatment. Symptomatic effects focus on only one symptom at a time, and disease-modifying effects focus on multiple domains, which brings us back to the GST and why a GST is an appropriate measure.
This next slide shows what an effect would look like if you had both symptomatic and disease-modifying effects. So the blue line at the bottom is a placebo or untreated group. The red line is a symptomatic treatment where you have just some number of points benefit over any time point in the disease. It's essentially a parallel line. And then the green line shows a disease-modifying effect where we've slowed down the rate of progression. Now, the yellow line at the top shows the ideal treatment effect, which would be a combination of both a disease-modifying effect and a treatment effect or and a disease-modifying effect. So you get the immediate benefit of the symptom benefit, but you also get the slower rate of progression that you would get with disease modification.
That type of treatment effect would be the best kind of effect for patients in any stage of Alzheimer's disease. This next slide then shows what happens if treatment is stopped with any of these patterns. What you see is with the blue line that receives no treatment and then the symptomatic line, the red group that goes up and then drops back down when treatment is removed, they both end up at the same point because the symptomatic treatment just goes away when treatment is removed. But both the disease-modifying effect and the disease-modifying plus symptomatic effect, the disease-modifying portion of that effect is maintained. So both of those groups keep the disease-modifying portion of the effect that they gained during the first phase. Then they both progress as a normal patient from that point on with a parallel slope to the original placebo decline.
Next slide. So with a progressive disease, if we assume that it's declining linearly over time, we can talk about % slowing. 100% slowing would mean we completely halt the disease, and there's no progression at all in the active arm, and the placebo group continues to decline. And then when we talk about a 50% slowing, what we mean is that the progression in the active arm is half of what it is in the placebo arm. And in this case, we show a 4-point decline in the placebo arm and then a 2-point decline in the active arm, meaning that we have 50% slowing, 2 points of progression out of 4 points that the placebo group progressed. This also shows with the green line a 33% slowing, which is 1.3 points of difference out of 4 points of placebo decline.
So again, we prevented 2/3 or sorry, we prevented 1/3 of the decline, and they continue to progress at 2/3 the rate they would have otherwise. Next slide. So we like to talk about time savings. And this seems like a bit of a jump, but the reason we like to talk about time savings is if you are slowing down a degenerative disease with a disease-modifying effect, what we really want to measure is how fast the disease is progressing. Are we saving people time in terms of the rate of progression of their disease? If we can slow down the true progression of the disease, then we have a disease-modifying effect, and we can measure how much time we've saved people with this new intervention. Next slide.
So this shows a GST where we would have—and this is just simulated data—and this shows a GST where maybe our ADL outcome has variability. It's a small sample size, and we get an effect that's in favor of active treatment, but not quite statistically significant. Our p-value is 0.09. And then the cognitive assessment here, also in favor of active, similar magnitude of effect, very consistent results across the two endpoints, p-value of 0.06. In that case, we wouldn't get significance on either of the two endpoints, but the consistency of the effect size and the consistency of the magnitude across the two, when we put it together into a GST, would give us statistical significance. And we have a p-value here with the two together of 0.03.
Now, on the right, I want to point out here we have GST values shown here that are similar to the ones that we might see in this study. Effect size is 0.28 and 0.32 and 0.30. Now, GSTs are measured in standard deviation units. And what that means is that it can be interpreted similarly to a Cohen's D. Cohen's D of 0.2-0.3 is a size that's normally seen with treatment effects in Alzheimer's disease. And these effects are considered meaningful in terms of the treatment benefit that's seen. So with these two, we have a 0.28 standard effect on the GST for the ADLs, a 0.32 standard effect for the cognitive assessment, and then it comes together into the GST with a 0.3 overall GST score.
This shows the same two lines that we had before, which is the 50% slowing and the 33% slowing of progression. But now, instead of looking at the vertical point difference between the lines, we want to look at the horizontal difference between the lines. So if we come to the end of the active group here and we ask the question, the active group at the end of this study is at a score of two points. At what time during the study was the placebo group at that same two-point decline? And we draw a line horizontally backward where it meets the blue line, and we see that the placebo group already had two points of decline at six months. What that means is that the active group has been saved half of the progression, and in this case, has been saved six months of progression.
They've only progressed six months in the disease during 12 months of time passing. We can do the same thing with the green line where we show that the placebo group is again at four points at the end of the study. The active arm here is two and two-thirds points. If we draw the line horizontally backward, the placebo group was at two and two-thirds points at about eight months, which means we've saved four months during 12 months of treatment. That's a 33% time savings. We've saved them 33% of the time out of that year in terms of their progression. If we have horizontal—or sorry, if we have linear progression over time, then our percent slowing on the point scale is exactly the same as the percent slowing on the time scale. Time is a very easy interpretation.
If you tell a person, "I changed your score by 2 points on the ADAS-Cog," they may not have any idea what you're saying. But if you say, "We saved someone 4 months of progression with 1 year of treatment," they would know what that means for a patient. Next slide. So conclusions. GSTs measure the effect on the whole disease. When we think we have a disease-modifying effect or a disease-modifying effect plus a symptomatic benefit, we really want to measure the effect we have on the whole disease and not just a single symptom or even 1 or 2 symptoms individually. GSTs are particularly relevant for disease-modifying treatments or combinations that are symptomatic and disease-modifying. GST effect sizes can be described with % slowing, with 100% slowing meaning no progression in the active arm at all, 50% slowing meaning half the progression in the active arm.
That's an easy thing to interpret as well. If you can tell someone we've had a 33% slowing of the treatment or of the progression rate in the disease, that's easy to understand. GSTs can also be used with time savings for interpretation. If we have linearity, then a 50% slowing means 3 months of time saved with 6 months of treatment. So we've saved half of the progression time that they would have had if they had been on the placebo. Time savings is interpretable to patients, care partners, and clinicians, and is an easy way to interpret the GST effects. And with that, I will hand over to my colleague, Anton, for his presentation.
Thanks, Suzanne. And everyone, good afternoon to many and good morning to the others. I'm going to talk about the medical need and current treatment landscape in mild to moderate Alzheimer's disease.
Next slide, please. If we think about Alzheimer's disease, then basically, this is a growing problem. It's not limited to the U.S. or to the Western Hemisphere. This is a worldwide problem. Actually, the growth in numbers is somewhat greater in the rest of the world. We have 50 million people with dementia currently worldwide, and it's expected to triple by the year 2050, so to about 150 million. Alzheimer's disease is probably about three-quarters of this case being fairly pure Alzheimer's disease pathology, another 5%-10% being Alzheimer's disease mixed in with other pathology. It's a major cause of disability among older people, and the physical, psychological, social, and economic impact is tremendous, not only for the patients, but also for the families, the care partners, for society at large.
If we look at the USA, then basically, we have just under 7 million individuals with Alzheimer's disease or related dementias, and it's expected to double over the same timeframe, so by 2050. In the US, it's the sixth leading cause of death, and it kills more individuals than breast cancer and prostate cancer combined. The cost is astronomical, $305 billion in 2020, growing rapidly, expecting to be about $1.1 trillion by 2050. Only a small amount of this is because of medical costs or direct medical care for the Alzheimer's disease itself. It's the loss of productivity, the fact that this disease requires you to have a caregiver or a care partner from relatively early in the clinical stage of the disease that also loses their productivity and earnings ability. That is reflected by an enormous amount of unpaid service.
Beyond the numbers that I just talked about, Alzheimer's disease is the disease that actually most people fear more than any others. There is now data that suggests that people in middle age fear Alzheimer's disease more than cancer. You can understand that when in the last 20-30 years, cancer has moved from a 25%-75% five-year survival. But with Alzheimer's disease, there is maybe the possibility of delaying progression, but we can't basically reverse the disease at this point. And so it's a disease of personal frustration and despair. People talk about the fact that they lose themselves. They're not going to be who they perceive themselves to be, and they become a burden to their loved ones and to society.
There is tremendous stigma still, and I think that it translates actually into how medical care is considered and paid for this group. There's isolation and loneliness. There's insufficient attention by most physicians. The treatment options are limited. The care and support services are tremendously fragmented, and there's a rare community that actually excels at this. The stress and the impact on just the family dynamics is tremendous. We see so much that care partners may suffer in terms of their own health. It creates family discord. I am helping more than you, and you're not stepping up. That this kind of family breakdown can outlast the lifespan of the patient. Next slide, please. What we now know is that Alzheimer's disease is a different disease than we thought 30 years ago, even 20 years ago.
At that point, we really only focused on the dementia stage of Alzheimer's disease that we often refer to as Alzheimer's dementia. But that is actually a late development in the disease. We have now three stages that are identified: the pre-symptomatic or preclinical stage that often goes on for 20, 25 years before the emergence of any clinical symptoms. What that means is that if you're going to get the clinical symptoms of Alzheimer's disease at age 75 or 80, the changes in your brain, the proteinopathies that I'll talk about a little bit later, start maybe around age 50, 55. And during this time, there's a relentless onslaught. In fact, by the time that you have a clinical form of Alzheimer's disease, you've lost about 50% of your neurons. And so these brain changes, they evolve, they continue, and they, like I said, are just relentless.
All these changes end up leading to the mild cognitive impairment stage of Alzheimer's disease. Basically, that's when we see the first symptoms. These symptoms are often quite mild, and we have a problem actually in basically distinguishing between mild cognitive impairment and normal aging. Some of the symptoms are quite similar: a little bit of forgetfulness, maybe a lower bandwidth in terms of speed or processing, which may look like you don't have the same decision-making capability as you used to, and kind of consistent forgetfulness. These are things that normal people experience as they get older. At this stage of disease, we also have no functional impairment. Maybe the biggest contributor to accurate diagnosis of mild cognitive impairment is the use of biomarkers.
Mild Cognitive Impairment due to Alzheimer's disease that is driven by the pathological changes in the brain that are consistent with Alzheimer's disease ultimately leads to the dementia stage. The dementia stage has more cognitive impairment, so more persistent short-term memory difficulties, more impairment in logic, reasoning, and decision-making, more language impairment, predominantly difficulty finding the right words and expressing yourself, but later in the disease, difficulties in understanding what is being said to you, as well as visual-spatial dysfunction. That is, problems with navigating, problems recognizing landmarks, problems recognizing faces. We talk about the mild, moderate, and severe stage of Alzheimer's disease. In the mild stage, you have no functional impairment. That's what sets it apart from Mild Cognitive Impairment. So you start to lose the ability to manage your usual daily chores and activities.
In the moderate stage, you have much more significant impairment in your functional abilities, and you are truly dependent on having someone around 24/7, not necessarily to assist you with everything hands-on, but to give you guidance, support, structure, reminders. In the severe stage of Alzheimer's disease, you need hands-on assistance with this. Next slide, please. What are the changes in the brain that typify Alzheimer's disease? The one that is spoken about the most is amyloidosis or cerebral amyloidosis. That is the buildup of the toxic form of beta-amyloid, so A beta 42, which originally is in a soluble form and polymerizes and forms oligomers and protofibrils and ultimately amyloid plaques. It's the first change that we can truly identify with biomarkers, and we can identify it while you're alive with amyloid PET scans, with then fluid biomarkers from cerebrospinal fluid, as well as blood biomarkers.
As amyloidosis builds, it triggers other things. As we start to see clinical symptoms, we start to see an increase in tau, particularly phospho-tau, which is basically the phosphorylation of the tau protein, which leads to its loss of normal function. We start seeing tau tangles in the brain. The emergence and progression of clinical symptoms correlate much closer to tau than it actually does to cerebral amyloidosis. When you have MCI, you basically have a fully saturated brain of amyloid, but tau kind of is beginning to escalate at that point. Like I said, it correlates very closely with clinical symptoms. Now, what we know from studies of older individuals and particularly superagers is that there is a group of individuals that can have amyloid plaques and tau tangles but have no clinical symptoms.
You can follow them, and there is a buildup in both, but they have no clinical symptoms. What sets these individuals apart is that they tend to not have any neuroinflammation and therefore much less impairment in synapse density, etc., etc. Amyloidosis, tau tangles associated with neuroinflammation as well as metabolic disruption, oxidative stress, leads to neurodegeneration or loss of brain cells and loss of synapses, the connections between neurons. The neurons that are left even don't communicate very well. We also start to see a breakdown in the amount and the integrity of neurotransmitters that help the neurons communicate with each other. You saw in Javier's presentation some of the biomarkers that we look for and actually the impact of fosgonimeton on markers of neurodegeneration, neuroinflammation, and possibly metabolic disruption.
Cognitive and functional decline is a late emergence in all of this and arises from the relentless progression of the processes that I just mentioned. Next slide, please. So if we look at mild to moderate Alzheimer's disease, and I want to highlight that I'm not talking about early symptomatic Alzheimer's disease right now. I'm talking about mild to moderate disease. Approved therapies for mild to moderate Alzheimer's disease are the cholinesterase inhibitors that have been around since the late 1990s and memantine, which has been around since the early 2000s. We've had nothing come to the market that targets people with mild to moderate Alzheimer's disease, neither symptomatic nor disease-modifying in that timeframe. Next slide, please. So these approved symptomatic treatments, they basically have a modest impact, and they do not really have any meaningful impact on the underlying brain pathology.
When we talk about the humanized monoclonal antibodies that have been catching so much interest, and aptly so, it's important to remember that those are approved for earlier stages of disease, so early symptomatic Alzheimer's disease. I hope to show you actually why I think that that matters as well. Next slide, please. So the cholinesterase inhibitors are not completely benign. They have a number of side effects that about 20% of people experience. At least 10% have to go off these medications because we can't work around it. GI symptoms like nausea, vomiting, and loss of appetite and weight loss, dizziness, and syncope, particularly because of slowing of heart rates, leg cramps. And with memantine, we can see confusion. We can see sedation and dizziness in particular. Next slide, please. So can you click one more time and one more time? Yes. Thank you. Go back.
So let's look at again the hallmarks of the disease and what brings Alzheimer's disease to bear. I've talked about the beta-amyloid. I've talked about the tau pathology, so the oligomers, the protofibrils, and the amyloid plaques, as well as the tau tangles. But we need to basically bring into this neuroinflammation, accelerated neuronal death, oxidative stress, and the synaptic dysfunction because that is one of the main things that kind of drive the cellular loss in Alzheimer's disease. Next slide, please. So there are no disease-modifying therapies for mild to moderate Alzheimer's disease. And you basically saw Suzanne's presentation previously. What would be an optimal treatment in this stage of disease? And I'll explain that further.
It is actually an intervention that both has a symptomatic benefit as well as disease modification that maybe restores the synapses, decreases neuroinflammation, improves the communication between neurons in addition to kind of modulating the kind of death cycle that we end up in here. Next slide, please. So why do we need disease-modifying drugs in this stage of the disease? Because it's probably some of the most distressing stage of disease in Alzheimer's disease. At this point, it's clearly that this is a disabling and ultimately fatal dementing disease that we're seeing increasing significantly in incidence because the population is aging and the economic and societal burden is striking. And it makes as much difference. And maybe the cost savings in some ways are easily more easily realized at this stage of disease than at, for example, preclinical stage or even early symptomatic stage. Next slide, please.
So if you delay the onset and the progression of Alzheimer's disease by only two years, you can have a massive impact on the overall reduction in global burden. And that is what we can do. We can bend the curve with medications that don't necessarily need to kind of cure the disease, but a meaningful impact that maybe improves symptoms and delays progression will have a marked societal impact. Again, what I wanted to highlight is why is it that I am harping on people with mild to moderate Alzheimer's disease? When you see progression, clinical progression in Alzheimer's disease, and that's different than the pathological progression, we often talk about a hockey stick. And sometimes we say we can take two hockey sticks and have the blade up and the blade down. And that is that in the early symptomatic stage, the decline can be very, very slow.
Once you hit late mild stage and moderate disease, you start to see an acceleration of clinical decline. That is, you go from the blade and you start sliding down the handle of the hockey stick. And then as you hit the severe stage, particularly if you don't have major medical complications, it looks as if the disease starts kind of slowing down. Maybe it's artificial because you've lost so much function at that time that we have a hard time picking that up. But the mild to moderate stage is really the point of most accelerated disease progression. There are few treatment options, no disease-modifying treatments. This is when you just see how people are eroding in terms of their abilities, cognitive abilities, and functional abilities. And the distress for both patients and families becomes so striking. Next slide, please.
So I think that the treatments that go for mild to moderate disease and may have a symptomatic improvement, even if the cholinesterase inhibitors and memantine have symptomatic improvement, we can look at medications that either could be added, like fosgonimeton and memantine maybe, or replace these treatments that often that you may not tolerate, that you may stay on for a while. But regrettably, we see a lot of people kind of stop treatment. A lot of doctors don't encourage people to stay on treatment long enough. There's just this gap that we have that we probably won't in the near term see the amyloid plaque targeting antibodies move into, that the later in the mild stage or moderate stage, the less benefit they may bring to the table.
So I think that treatments that maybe hit the crossroad receptor complexes or neurotransmitters that are highly relevant in this stage of disease, that looks very attractive to me because this is the group that we have easily identified where basically, particularly in communities where biomarkers may not be as readily available going forward, this will be a sweet spot and a high-need area. Next slide, please. So with what you've heard about fosgonimeton and with what you know about HGF/MET and the potential downstream effect of modulating that receptor, we have a drug that has the possibility of being disease-modifying, possibility of enhancing cognition and function, has the possibility of reducing neuroinflammation, and prevent nerve cell death. We have the ACT-AD study that really informed us about how to enrich and enhance the probability of the ACT-AD study that really enhances the LIFT-AD study.
I think that the interim analysis gives me at least a little bit of comfort. This is a clinical trial, but at least there was no futility that was met at that point. It covers an area where there's a high unmet need and enormous potential market. I want to highlight that a little bit, that remember what I said about worldwide, that we have 50 million people worldwide, and those numbers are growing even more. There, early diagnosis is much less common. Biomarker availability is much less available. Infusions that require regular MRI monitoring, so this high intensity and then dealing with ARIA may be quite challenging. It won't be as easy moving the beta-amyloid plaque targeting humanized monoclonal antibodies in this space. A subcutaneous injection or an oral medication that doesn't require detailed MRI monitoring might be easier to use.
Next slide, please. So if we look at all of this together, I hope you understand what I'm excited about seeing the LIFT-AD data, not only because we need to have options that go above and beyond amyloid and tau. We need options that may not be quite as cumbersome and use as much bandwidth in the medical system. But most of all, we need something to offer our patients with Alzheimer's disease. This is an ugly disease. It's disabling and ultimately fatal. It's increasing in numbers due to the aging of the population. The economic and societal burden is astronomical. In fact, in 2050, there will be more people with Alzheimer's disease living in China than all the populace of California, just to kind of point out the numbers here, and that we don't need to bend the curve so much to make a major difference.
This is a disease that hits you later in life. So delaying onset 2 years, even if we could get 5 years, or keeping you in the earlier stages longer will have a very meaningful impact. And fosgonimeton, if shown to be effective, has the potential to slow to bring about some symptomatic benefits, slow clinical decline. And then, as you heard from Suzanne, basically buy you time in milder stages of disease where you still have some meaningful intact cognitive abilities and preserve your autonomy and likely decrease the emergence of behavioral symptoms. That is it. I think that's the last slide. And I thank you for your attention. Appreciate it.
All right. So thank you so much to both Suzanne for such a clear presentation of how to understand GST and put it in clinical context, and also Anton for just a state-of-the-art presentation in Alzheimer's disease.
Really, really thank you, both of you. So I'll kick off the Q&A session. And the first question is for you, Anton. And this has to do with something. You started your presentation and you ended the presentation with a concept about the impact of Alzheimer's disease globally as we move forward 10, 20, 30 years, and you provided the numbers. We typically start thinking about the U.S. market, but I wonder how you see a drug like this. How can it impact globally, regions beyond the U.S., Europe, Latin America, Asia? How do you see an intervention like that in this particular stage of the disease, mild to moderate, moving forward globally?
Thanks, Javier. And basically, I think the big issue there is that, look, I welcome any and every therapeutic option in Alzheimer's disease.
I'm certainly excited about the emergence and the opportunities that we have, for example, with the beta-amyloid targeting antibodies. But they're not going to be a fix. They slow decline, depending on the measure, by 30%-50%. People don't see a short-term improvement, which often kind of may have an impact on their compliance. And what am I getting from this? And you kind of have to say, well, it's an article of faith. We can look at basically the humanized monoclonal antibodies, and we see that even in Europe, they are much slower to move forward with approving lecanemab, which has been on the market here for almost a year now. And I think it is likely to be similar with donanemab.
Part of it is that their regulatory process is different, but they're also worried about basically whether the system has the bandwidth to provide these complex treatments. And those are communities that are well-resourced in terms of healthcare. You talk about countries that are maybe less resourced in terms of MRI scanners or infusion centers or expert clinicians. And that's the vast majority of the world. And it will be harder for the treatments that require really a very high level of sophisticated management and intervention to bring that in.
So I think medications, be that oral medications or injectables - and I want to make a distinction between injectables and medications that have to be given by infusions, maybe at infusion centers - that if you don't require very complex medical monitoring, if you don't require regular MRI scans, etc., etc., then having a disease-modifying treatment option that is kind of free of that will definitely become a very appealing option for particularly less well-resourced societies. And this is basically the bulk of the human population in the world that I pointed out in my first slide is a group where we're seeing an even more rapid increase in the number of people with Alzheimer's disease. And this will create very, very significant burdens for those societies, some of which are seeing slow rejuvenation, so low birth rates, and rapid graying of society.
So we have to give options that kind of provide those kind of worldwide solutions as well. Great.
Hey, due to time, let's go to some of our analyst questions.
Thank you. As a reminder for any analysts, please click the raise your hand button at the bottom of the Zoom window to be added into the queue. Our first question comes from Graig Suvannavejh from Mizuho. Graig, please unmute your microphone. You may proceed.
Hi, can you hear me? Yeah. Yes. This is Charles off of Graig. So two quick questions from us. How are subgroup analyses integrated into the GST, if at all? And two, can you describe any sensitivity analyses that will be used to examine the GST? Thank you. Sure.
So the first question is the interim analysis was done specifically in the subgroup of patients that were not treated with cholinesterase inhibitor, a total of 100 patients. We did combine the 70 and the 40 milligram doses, and of course, the placebo, so about one-third of each group. So that was the analysis that triggered the recommendation from the DMC. And the second question was, remind me, related to?
Yeah. The second question, I believe, was on what is the sensitivity analysis that we're going to do with the GST?
Well, so this study, we have a primary population. The primary population would be 40 milligrams versus placebo, non-acetylcholinesterase inhibitors. But as I showed you, we have a much larger population. So it will be a number of sensitivity analyses by different degree of baseline disease characteristics, maybe pulling the 70 and 40 milligrams, and a few others.
We're right now finalizing the SAP, in which we will describe precisely other potential sensitivity analyses and subgroup analyses that probably would be very, very helpful.
Great. Thank you.
Our next question comes from Jason Butler from JMP Securities. Jason, please unmute your mic. You may proceed.
Hi. Thanks for taking the question. I appreciate all of the detail you went into here. I had one for Dr. Hendrix. Just wondering if Dr. Hendrix could provide your opinions on the interim analysis itself and how that, in your mind, impacts the probability of success of hitting the GST in the LIFT trial. Thank you.
Yeah, certainly. Thanks for the question.
So anytime you do an interim analysis that's looking at whether the sample size needs to be increased, whether the study can continue as is, or whether we're in a range where there's really not much chance for success, getting past that analysis gives you more confidence in the results. It depends on exactly where the lines are drawn, how much more confidence it gives you. But certainly, getting past that threshold does indicate more likely success than just when the study started.
Thank you.
Our next question comes from Andrew Tsai from Jefferies. Andrew, please unmute your microphone. You may proceed.
Thanks. Thank you, guys, for hosting this webinar. Two questions. The first one is around LIFT-AD. Just curious, what is the minimum placebo-adjusted delta needed on ADAS-COG and ADL for GST to be stat sig?
How small of a trend can we afford to see on both of these secondary endpoints for GST to be stat sig?
The question is a good question. We haven't really gone into the specifics. But what we're really trying to do, and we talked about this today over and over again, is essentially halt the disease. And what we've been sort of thinking about in both ADAS-Cog and ADL, just to simplify, is if you look historically in mild to moderate patients, in a 6-month time frame, they roughly decline about 2 points in each of these scales, roughly. Our goal is to keep them and maintain them so they do not have that 2-point decline. That's roughly what we've been our goal is. And we are very hopeful that we can show that with the GST in this study in LIFT. Yeah.
And Mark, if I can add, maybe as Suzanne is, one key feature about GST is that you need to have directionally positive data in both. So it's not just because one will be skewed one way and the other you will hit that. And I think it's a critical component of this methodology. I don't know, Suzanne, if you wanted to add to that concept.
Yeah, certainly. So whatever power you would have with one of the endpoints, when you put the two together and you have a similar effect size across the two, you will have better power with the two together. And what that means is that you will be able to statistically detect an effect size that's smaller with the two together than you would with each of the individual outcomes.
That really comes from just reducing the variability by having consistency across the outcomes and then putting the two of them together.
Thank you. For the doctor, would you say a 2-point change at month 6 for both ADAS-COG and ADL would be meaningful? Or would you like to see a greater amount?
So thanks, Andrew. Basically, if you look at these scales and you look at where we are coming from, if we think about the cholinesterase inhibitors in about 6-month trials, they showed about a 2-3-point on average change on the ADAS-COG. So about 2.7 is the mean. I think here we may see with this population of mild to moderate disease a little faster decline than we heard Mark describe. And it is two things that I want to point out.
One is basically, are we just going to see a symptomatic separation, but that after the first 6-12 weeks, that the decline is basically progressing at the same slope between the drug and placebo group? Or are we seeing a steady growing separation between drug and placebo? And if you look at the ACT-AD data that Javier showed in terms of the ADAS-COG, you will see that the error bars stopped overlapping in the subgroup of cholinesterase inhibitors; more kind of, there was a growing separation as we went through. I think that many people are kind of benchmarked to three points on the ADAS-COG. I would love to see three points, but mostly here, what I want to see is this a phase II/3 study. I want to see a clear signal. I want to see a clear message.
I would love to see a signal on the ADAS-COG. I'd love to see a corresponding signal on the ADL. I would prefer if we saw a symptomatic enhancement and then a growing separation. Because at that point, we're talking about something that clearly is distinct from historical medications, be that the cholinesterase inhibitors or memantine. So the devil here is in the detail. I'll also be pretty frank that right now I'm at a stage where I see that statistically significant separation that will be accepted by the FDA is something that I get excited about. But also something that truly informs us about the molecule and how to move forward with development, understanding if there are subpopulations that are particularly attractive for this intervention, etc., etc. I know, Andrew, that that goes well beyond the simple question that you asked me.
But it doesn't really have a simple answer. Because I think that just benchmarking this to what people often throw around three points, because that's what was seen in one of the studies with the cholinesterase inhibitors 20-something years ago, that just means we're kind of stuck in the past.
Makes sense. Thank you.
There's one other thing I would love to add. I totally agree with you. Because I do think, and a lot of times we ignore this, is that the biomarkers and looking at the biology is going to be very important. If we can show reduction in NfL or reduction in A beta as measured by a 42/40 ratio, and in fact, reduction in inflammation, it really starts to prove that this is disease-modifying and has the potential for even greater improvement over the long term.
And can I just chime in too?
The monoclonal antibodies are seeing 20%-30% slowing, maybe 40% at the most. So even a 1-point slowing with a 2-point progression of placebo would already be the largest disease-slowing effect we've seen. So I think it's highly unlikely that if we get statistical significance on the GST, that we would be in the range where clinical meaningfulness could get in the way of regulatory evaluation.
Very well. Thank you.
Our next question comes from Corinne Jenkins from Goldman Sachs. Corinne, please unmute your microphone. You may proceed.
Good afternoon. Can you all hear me? Yes. Yes. So I guess, Dr. Porsteinsson, from your experience managing patients, do you see correlations between the decline in ADAS-Cog and ADL typically?
Yes, we do see these things correlate. It's not 100% correlation, but you usually see if there's a discordance, just wait.
Basically, it always worries me if I see, for example, someone manage functionally better than their cognitive scores show, that we're going to see a relative acceleration of functional loss over the next six months and vice versa, that these things ultimately will move together. It won't be smooth. It won't be exact. I think that one of the things you heard from Suzanne is that by combining these two measures into the GST, you even out some of the variance that may emerge. That's what I feel that composites are particularly helpful with, is kind of decrease the noise that gets into the data. It's particularly important early on in the development because it may help you avoid making rash decisions that weren't well-founded, such as stopping a study when you looked at too narrow a measure.
But you usually see these go relatively hand in hand, but it's not smooth. Over time, it kind of begins to look smooth, but there's not a perfect correlation.
I would just comment that the six-month correlation and change scores between the two is about 0.3. The longer you go, the higher those correlations get. 0.3 correlation means they only overlap about 10%. And that's because the noise is so prominent at six months, and that's why we're really putting the two together in a GST.
Got it. Maybe just one more then. As you mentioned, you had an independent analysis of the LIFT-AD data and analyzed the data in kind of an unblinded manner and determined you could continue the study. How did they establish futility for the study? What was the criteria in there? Could you provide a little bit more detail?
Yeah.
It was really just showing an improvement in GST, right? That was the futility. And in addition to that, there were limits put on the SOCs. Because we wanted to ensure just to ask the question, were we on the right track with fosgonimeton by itself? And then it has futility, i.e., was having an improvement on GST, i.e., was having an improvement on both cognition, ADAS-Cog11, and function as measured by ADL-23. And then there was a criterion, if the sample size is too large, then we wouldn't continue as well. And the results came back that we passed futility and we needed less than 150 patients to continue.
Got it. Thank you very much.
Our next question comes from Tom Shrader from BTIG. Tom, please unmute your mic. You may proceed.
Hi. You hear me okay? Thanks for all the background stuff.
Just a quick question for Dr. P. How are you going to use this drug around the acetylcholinesterase inhibitors given the interference? Does the Athira clinical package have to tell you that? Or are the acetylcholinesterase drugs do you give them to everyone? And so this would be a second drug, or are they not interesting and it's easy to push them out? Just going into the clinical data, how high is the bar for these things to be used first?
Yeah. So, Tom, absolutely. The cholinesterase inhibitors, for example, most people in the mild to moderate stage of illness are tried on a cholinesterase inhibitor. In the hands of memory experts, they tend to stay on these for quite a while because we historically haven't had other options. So we say, it's like an insurance, just stay with this.
In primary care offices, etc., where the bulk of people with Alzheimer's disease are currently cared for, the duration of treatment is much shorter. It's often as short as 6-12 months because they may not really emphasize stick with it. You may have only 50% of people that are on ongoing treatment with a cholinesterase inhibitor, but maybe 80% that have tried them at some time. Many of these individuals are looking for other options. It is an intriguing pharmacokinetic pharmacodynamic interaction between the cholinesterase inhibitors and fosgonimeton. I think that the big issue here is, though, what is fosgonimeton going to bring to the market? Is it going to look mostly like a cholinesterase inhibitor? Or is it going to look like a cholinesterase inhibitor plus? My hope is that we will see not only a symptomatic improvement, but a disease-modifying impact.
If we get that, then hopefully we will finally have something on the table that might disrupt the dominance of cholinesterase inhibitors right now. For that, we need to wait for the data. But it's important to have a story to tell. And it's important to have some hard data to bring to this conversation. But you want to be able to disrupt the current kind of 20-something year standard. It's distressing that we haven't gotten further along in that timeframe.
Thank you. A quick follow-up to Mark or Javier. Do you think you need in phase III to unravel whether it's just concomitant acetylcholinesterase inhibitor, or do they have to be acetylcholinesterase inhibitor naive for your drug to work? Do you think you need to unravel that in phase III?
I think that's a great question, Tom.
I think the LIFT study likely will have to consolidate what we learned today. If it's in fact clearly the effect is more prominent in those patients that are naive or not on cholinesterase inhibitor, when that might guide how to design the phase III study. Remember that we have about 200 of the 550 patients that did receive concomitant cholinesterase inhibitor. So one of the analyses, of course, will be include everybody and include those on and off. So I think the study, the LIFT study, and remember, it's a phase II study of 550 patients, it will answer that question and guide the specific design of the registration phase III program.
Great. Thank you for all the answers.
Our last question comes from Paul Matteis from Stifel. Paul, please unmute your microphone. You may proceed.
This is James. Thanks for taking our question. I'm on for Paul.
We just had a quick one. Just curious what recent kind of regulatory interactions you've had and what those discussions have looked like, if at all, and basically how you're thinking about the utility from a regulatory perspective, LIFT-AD. Basically, just wondering, I know historically it was talked about as potentially pivotal, and wondering if that's still the case just in light of all of the changes you've made. Thanks.
Yeah. Really good question. So we did meet with the FDA and got alignment on the LIFT-AD trial. Again, highlighting the fact that both ADAS-Cog11 and ADL-23 are validated and key endpoints that the FDA is interested in. If you take a second just to take a step back and really understand what the regulatory pathway has been recently for both of these monoclonal antibodies, I think it's good to put our program in perspective with that.
If you look at, let's talk just about the Eisai program. So Eisai was roughly two trials. They were able to get accelerated approval based on 2,600 patients in that neighborhood. If you look at the more recent discussion with Lilly and donanemab, they also greater than 2,000 patients. They asked the FDA for accelerated approval and were denied based on not having full-month exposure. So they increased that and, of course, submitted for full approval. We believe with our 550 patients, we are on our way, but it is highly likely that we will need another trial. I would also argue that, and we talked a lot about this today, that we are in the mild to moderate space. And the other thing that we haven't seen any of is ARIA. So we do not have that issue from a safety perspective.
So if that sort of helps, we believe that LIFT, we will learn a lot from it. And we're hopeful that it'll be one of our trials that we use for registration.
Thanks, Seth. Thank you.
Is that it for the questions? I think that's it. I'd like to just thank everyone first for joining us today. I'd like to thank our panelists. Thank you, Dr. Hendrix. Thank you, Dr. Thorsten for all of your discussion today. It was very helpful. And many thanks to everyone. And as we close, we're really excited for data readout coming fall. We're targeting fall. And we can't wait for our data. So thanks again for taking the time today.