Alterity Therapeutics Limited ($ATH)

Good afternoon, and welcome to the Alterity Therapeutics Virtual KOL Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Alterity website following the conclusion of the event. I'd now like to turn the call over to your host, Dr. David Stamler, Chief Executive Officer of Alterity Therapeutics. Please go ahead, David.

Thank you, Tara, and good afternoon. Good morning, everyone, and thank you very much for joining this call. We're really excited about the progress we've made on ATH434 for multiple system atrophy, and we're really fortunate today to have 2 clinical experts joining me to help put this disease in perspective and to talk a little bit about our data and our path forward to trying to address this significant unmet medical need for individuals with MSA. These are our forward-looking statements regarding -- sorry, we skip past those regarding investment. I encourage you to review these as well as information on our website. So as mentioned, joining me today is Roy Freeman, who is Professor of Neurology at Harvard Medical School. Dr. Freeman is an expert in autonomic neurology and has deep understanding of MSA and all aspects of it. And we'll talk about the agenda and what Roy will cover in a moment. In addition to that, Dr. Daniel Claassen is Professor of Neurology at Vanderbilt University. Dr. Claassen has been involved in our development program for several years, I'm starting with our natural history study and has been instrumental in both the clinical aspects of our program as well as the neuroimaging. And I think you'll get an opportunity to hear about some very exciting data regarding the Phase II study from Dr. Claassen. So after my brief introduction regarding ATH434, as referenced, Dr. Freeman will give an overview of multiple system atrophy and the unmet need to address these individuals decline. And then as I mentioned, Dr. Claassen will review some new insights on our Phase II data from -- that we disclosed last year. Finally, I will talk about our Phase III planning, discuss various aspects of the path forward, and we'll give a brief overview and update on where we have gone in the recent past with discussions with the FDA. So to just summarize the key aspects of the progress we've made over the last year or so, we have identified in our Phase II study, what I think is exceptional efficacy with 434 in MSA, demonstrating up to 48% slowing of disease progression when compared to placebo. And that's on an endpoint that is -- a functional endpoint that is recognized by the FDA as being very important to support a drug approval. In the same context, we demonstrated there was an excellent safety profile and no serious adverse events related to the drug. From an investor standpoint, this -- what this translates to is a significant commercial opportunity because there is nothing approved to address the underlying pathology of disease in these individuals. And as a consequence, if the drug is approved, then we do have significant potential for upside from an investment standpoint. We'll be talking mostly about not only the disease, but the drug ATH434, I sometimes refer to it as 434 is an iron chaperone. It is designed to bind and redistribute the excess iron that drives the pathology in MSA. And I'll tell you more about the attributes of the drug itself. And then finally, based on our Phase II results and our recent interactions with the FDA and our upcoming interaction with them mid-year regarding the Phase III program, we expect to be advancing rapidly to Phase III in the near-term. So before I talk about how ATH434 works, I just want to set the stage a little bit about the pathology of this disease. There are 2 key aspects that we target. One is alpha-synuclein. And for those of you not familiar with the story, alpha-synuclein is an important protein that is present in all neurons and facilitates neurons to communicate with one another. However, in diseases like MSA, alpha-synuclein aggregates, and when it aggregates, it can't function properly and that underlies the dysfunction that occurs in individuals with this disease. In addition, we also target iron, and we target alpha-synuclein and iron by redistributing this excess iron. Now before talking about the excess iron, iron is important for all forms of life, not only for energy production and enzyme activity and oxygen transport, things that you've probably heard of. But in the central nervous system, iron is very important for synthesis of neurotransmitters like dopamine. And it's also important for the synthesis of myelin, which is the fatty sheath that wraps around the nerve terminals or the axons and enables rapid neurotransmission. In disease, however, there is excess amounts of iron in the areas of pathology. And this is really what we're aiming to target to try and reduce the sources of pathology in MSA. I think this -- what you see now on the slide is a very interesting study that was done several years ago that looked at -- this is an autopsy study. So it looked at the brains of individuals that died from MSA. And what you see in the slide are patients in blue with age-matched controls in gray. And we see that in the areas of pathology, there is iron accumulation compared to patients of a similar age. And this is really what we are trying to prevent with our therapy. We think this excess iron is driving the pathology, and we're aiming to augment the endogenous systems for managing that iron. Now that's an autopsy study on the left. On the right is an image from a specialized method called QSM that Dr. Claassen will talk about. But this is a tool that we can use to actually measure the iron in the brains of patients -- of living patients. And this is something that we actually implemented in our clinical trial, and it really gives us an insight in terms of how the drug is working. So to try and put this in perspective, as mentioned, for a variety of reasons, there is abnormal control or disruptive control of iron in the central nervous system that leads to excess amounts of the so-called reactive iron or FE2+. And normally, that's handled by these endogenous iron chaperones called PCBPs. That's I know a bit of a mouthful. But when there is excess amounts of iron and excess labile iron, it actually drives pathology. So you can see along the top half that excess iron can actually promote alpha-synuclein to aggregate. And those aggregates of alpha-synuclein can actually damage intracellular structures like DNA or mitochondria. And that aggregated synuclein can actually penetrate the nucleus and kill the neuron. In addition, because of that toxicity to neurons, there are these support cells in the central nervous system that actually scavenge that alpha-synuclein from the neurons. And in doing so, while they preserve the neurons, they too become overloaded with that aggregated synuclein and they are impaired and then they can't myelinate the neurons properly, which then ultimately contributes to impaired neurotransmission. So that's one pathway of damage caused by the excess iron. The other pathway is that iron itself is the source for free radicals. So the excess iron generates free radicals that do 2 things. Number one, they also promote the alpha-synuclein to aggregate. And then they also can damage the intracellular structures that I talked about of mitochondria and cause lipid peroxidation in a process that's referred to as ferroptosis that ultimately leads to cell damage and cell death. So what we're really trying to do is to target this iron in the disease. And this is kind of the cycle that we're trying to break. The reactive iron that I mentioned that's present in excess will generate free radicals. Those free radicals will actually cause alpha-synuclein to aggregate, the reactive iron itself will cause alpha-synuclein to aggregate. And then when alpha-synuclein aggregates, it is tried to -- it's cleared by cells, and that can actually lead to other cellular dysfunction that can propagate the cycle and lead to more reactive iron or more free radicals. So what we're really trying to do is break this cycle. So to tie this all together, ATH434 will chaperone excess labile iron within the central nervous system. In doing so, it will reduce alpha-synuclein aggregation and oxidative injury. And we've shown this nicely in multiple animal models of MSA. And then in doing so, that will preserve neurons and their support cells with the ultimate goal of stabilizing function or slowing its decline. And based on all these mechanisms and the fact that 434 does not have off-target activity in terms of stimulating neurotransmitters or receptors, we believe that 434 is indeed a potential disease-modifying therapy. So before I turn it over to Dr. Freeman to give an overview of MSA, just to orient you to 434 itself. This is a small molecule drug candidate, which means it can be orally administered, and that's preferred by patients and physicians. The drug has been shown to nicely cross the blood-brain barrier in multiple animal models as well as in humans. It can also penetrate cells where we think the key pathology is ongoing, as just discussed. And as I've mentioned, the drug is an iron chaperone, which means it has moderate affinity for binding iron and can redistribute that iron within the central nervous system. And Dr. Claassen will show you some interesting data to support that notion. I haven't talked about it, but in addition to multiple system atrophy based on similarities in pathology, ATH434 has potential to treat other synuclein-related diseases like Parkinson's disease and other iron-related diseases like Friedreich's ataxia. So it really does have a broad treatment potential. And then finally, the drug does have orphan drug designation in the United States as well as in Europe. And based on its potential to address the significant unmet need in MSA, we also have Fast Track designation through the FDA, which gives us various efficiencies and various opportunities to interact more efficiently with the FDA. So I will stop there, and then I'm pleased to turn it over to Dr. Freeman, who's going to educate you a bit on multiple system atrophy. Dr. Freeman?

Thank you. Thank you, David, and thank you, everybody, for listening in anticipation. So I'm going to give an overview of MSA, but I think the view from the top, this is a devastating disease for which there is no disease-modifying therapy. There's no therapy that changes the natural history of the disease. And that is the underlying point that I think you should carry with you throughout this presentation. So now for a little background in the disease itself. This is, as David mentioned, a rare orphan progressive neurodegenerative disease characterized as the name implies by several systems being involved: Parkinsonism, the extrapyramidal system; cerebellar dysfunction; and dysautonomia. So affecting mobility, gait, coordination and also the automatic functions. And each one of those core characteristics has an important differential diagnosis, which is to say that needless to say, all forms of Parkinsonism are not due to Parkinson's disease. There is, of course, multiple system atrophy, but also dementia with Lewy body and a number of other diseases as well, such as progressive supranuclear palsy, frontotemporal lobar dementia and so on. And those all should be taken into account when a patient with possibly multiple system atrophy presents. Now this is a rare disease. Here, you see the annual incidence extremely low, prevalence extremely low, and it fits the characteristics of an orphan disease with less than 50,000 individuals in the United States. Now the mean age of onset is in the sixth decade and both sexes are affected equally. Important to note, and this is when I mentioned earlier that this is a devastating neurodegenerative disease, survival after the onset of symptoms is between 6 and 10 years. David gave you a beautiful overview of the biology of synuclein and multiple system atrophy is one of these synucleinopathies. There are several, as I mentioned, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy and pure autonomic failure. Important to note that not all patients with Parkinsonism are synucleinopathies. I mentioned, for example, progressive supranuclear palsy. But these 4 of all proteinopathies, and they are characterized by the deposition of misfolded alpha-synuclein. And the pathological hallmark of multiple system atrophy is a specific cell -- the oligodendrocyte in which there is deposition of alpha-synuclein. And these are called glial or the oligodendrocyte is one of the family of neuroglial cells, and this is in contrast to the pathological hallmark in Parkinson's disease, which is the Lewy body. Now prompted by a number of studies, and this is just one of those, in which it was clear that in life, many patients. Here, you would see 62% only had the correct diagnosis of autopsy. Prompted by this paper and others, we decided that we needed to redevelop the diagnostic criteria that were used to diagnose multiple system atrophy. And we published a critique of those diagnostic criteria. And then in 1922, which I call these the new diagnostic criteria, they're not that new anymore, we published new diagnostic criteria for this disease. And these are the following. We divided the disease into 4 category, obviously, the gold standard neuropathologically established disease. But from the clinical standpoint, 2 categories, clinically established, which is highly specific and clinically probable, which is less specific, but has greater sensitivity. And clinical trials usually incorporate either one or both of those diagnostic categories. We also importantly introduced just because there is so much emphasis on diagnosing all neurodegenerative diseases at the earliest stage, whether this be Alzheimer's disease, Parkinson's disease or multiple system atrophy, we introduced a category called possible prodromal multiple system atrophy, the earliest stage, least specific but most sensitive. And these categories involve the core clinical features, the motor features seen on the left, the autonomic features, urinary symptoms often occurring very early and neurogenic orthostatic hypotension. There are a number of inclusion/exclusion criteria that go into developing these categories, and I won't go into them in the lecture, but should you wish, that article on the previous slide is available to read. So let's talk a little bit about the clinical course. I mentioned the diagnostic criteria. And I think what we know with this disease is it moves along aggressively and relentlessly. And it goes from the premotor symptoms, those are incorporated in the possible prodromal category, urinary dysfunction, a disorder of sleep in which people act up in dreams, REM sleep behavioral disorder and low blood pressure upon standing, orthostatic hypotension. Then the motor symptoms gradually develop with time. And over the course of several years, the patient will go from having mild mobility deficits to needing prosthetic support, walkers, canes to being in a wheelchair, which typically occurs after 6 or so years of the disease. Again, relentlessly progressive. What are the clinical trial outcomes that we use to measure the response to therapy or the natural history of the disease. And we have a rating scale that has been developed over a number of years. This is the standard scale used both in clinical, epidemiological and in disease-modifying studies such as the one David and Daniel are going to be talking about. This assesses disease severity and progression, and it is divided into 4 parts. First of all, the patient-reported outcome, most critical and most commonly used in disease-modifying studies just because the FDA is most interested in the way the patient feels and functions. Then there is a clinician-rated scale, the motor examination, the standard neurological examination, the autonomic examination and a global disability scale. Daniel Claassen is going to talk much more about this. The secondary outcomes, the UMSARS is typically the primary outcome is the global Part IV, which is a single measure of global disability. The OHQ, the Orthostatic Hypotension Questionnaire, which measures the symptoms of low blood pressure upon standing and also an activity scale measuring whether patients are able to walk or stand for a short or long time. Other criteria used in secondary outcomes are time to specific milestones. For example, how long does it take for the patient to be wheelchair dependent, quality of life, there is a disease-specific quality of life, the clinician global assessment of severity, MRI markers, Daniel Claassen is going to talk more about those and more recently, wearable digital outcomes, which provide a more objective measure of function. I want to talk briefly about biomarkers, and we divide biomarkers into several groups. Most relevant for this study is the diagnostic biomarker, but we also use biomarkers to prognosticate, to predict and also to measure response, pharmacodynamic biomarker, a measure of target engagement. And the biomarkers most likely widely used are imaging, more to come on that, seed amplification of alpha-synuclein, immunohistochemical detection of cutaneous deposition of phosphorylated alpha-synuclein, which is a highly sensitive and specific diagnostic biomarker. Happy to talk more about that, and then neurofilament light chain. Neurofilament light chain has become increasingly important, and I want to tell you a little about this and delay some misconceptions and simultaneously introduce the concepts that underlie this biomarker. Now neurofilament light chain is a structural protein of the neuronal cytoskeleton. You can see that in the figure at the bottom on the left. It's expressed in lung myelinated axons. These are the fast conducting axons, and those are the axons that are myelinated and are found in the white matter tract. This supports the stability of the axon, but when there is damage degeneration, neurofilament is released into the cerebrospinal fluid and into the blood. And as you see in the middle of that figure, damage, releasing neurofilaments, there's little blue strands, somewhat more in the CSF and less in the plasma. What do we know about this? Well, it's elevated in the CSF and serum/plasma in the setting of nerve damage, central nervous system damage. And this occurs across diseases from multiple system atrophy to multiple sclerosis. It is higher in multiple system atrophy than it is in Parkinson's disease, but there is an overlap with the other Parkinsonian disorders that I mentioned, progressive supranuclear palsy and corticobasal degeneration. There is a weak association with faster disease progression and shorter survival. Importantly, however, it is elevated early in multiple system atrophy, although as you see, if you look at the UMSARS I score, that measure of function, increasing over time over the first 4 years of the disease. It is high in the beginning but remains at that same high level. So not a surrogate marker for disease progression. Needless to say, lots more to talk about. Happy to answer any questions, but I think I probably used more time than I was allocated.

Thank you so much, Roy, for your excellent summary on MSA and really setting up my section of the talk, which is reviewing some of the important data updates for the 201 study, especially as we think about what these data mean for the Phase III study. So I first just want to remind people the design of the 201 study. So as you know, this was a randomized, double-blind, placebo-controlled study, and participants were randomized into either receiving 75 milligrams, 50 milligrams twice a day or placebo. It's important to note that we did a lot of preparation before this trial in that we ran a natural history study of patients that we called early MSA or possible MSA primarily to understand how some of the proposed biomarkers that I'm going to go with you today worked or early in disease. And we learned a lot about iron, how to measure it. We learned a lot about things like NfL, the clinical assessments that we used. And so on that left side, you can see that we had a -- the patients required to have a clinical diagnosis of MSA. We asked for them to have symptoms -- of motor symptoms only less than or equal to 4 years. And we excluded participants that had severe impairment. As you can imagine, patients that have severe impairment may not be able to tolerate a 52-week trial. And we also think that the drug would punitively help patients that were "earlier in disease" or with less severe impairment. The other novelties to the study is that we required participants to have elevated brain iron and MRI, I'll talk about that recently. We just got our paper accepted today, which goes through that methodology, and that was an important inclusion criteria. And then we required participants to have elevated plasma NfL, and this was helpful to increase the positive predictive value that participants actually had MSA. So all that to say, these participants enrolled over a year. Our main clinical endpoint was UMSARS I, and it's modified because we took out the sexual function question on that UMSARS I and all people generally do that now to -- because it doesn't change much, and it's very sex-specific oftentimes. We also included important secondary endpoints, the Clinical Global Impression of Severity, the OHSA, orthostatic hypertension scale, which really measures, have the severity of a participant's orthostatic symptoms. We included wearable sensors, and of course, we looked at safety of the drug. Our key biomarker for imaging was brain iron as measured by MRI. The substantia nigra was the predefined region of interest. I'm going to talk to you a little bit more about some of the learnings from this, but we did, for the first time in a global study, employ QSM imaging, iron imaging in clinical MSA. So this is also a tremendous accomplishment and learned a lot from this trial. So first, let's talk about some of the UMSARS I items, just so that you're aware of them. You can see these items are listed here. And these are things that are important to participants' function in MSA. Of course, speech, swallowing are clearly important in terms of bulbar or mouth and swallowing function that gets affected in MSA. Think about things that require dexterity, handwriting, cutting food, dressing, hygiene, all very important for a patient's function. Walking, falls are important to patients, orthostatic symptoms, low blood pressure, also urinary function and bowel function are critical to participants. And so these are interviews between the clinician and the patient and caregiver and then they are rated based on the severity of 0, meaning no severity up to 4, meaning maximal severity. So the higher the score of these total numbers, the worse the severity. Importantly, it's notable that there's a validated rating scale, validated and also accepted by the FDA as a clinical end point to support treatment of MSA. So in terms of the participants that entered this trial, generally, I would say that these were balanced between treated groups and placebos. You can see the ages, early 60s, majority male, about 2.5 years of motor symptoms. You can see the modified UMSARS I scores at baseline. You can see them generally balanced, representing mild to moderate symptoms of MSA. We employed a Parkinson's Plus scale, which is a clinical exam and the higher the score on this, the more evidence of clinical disease. And the reason why I include this scale is because one of the learnings we had in the natural history study was that quite a lot of patients are asymmetric in terms of their severity. There is a motor scale for UMSARS II, but it does not capture that asymmetry, it just rates the worst one. And we thought given the fact that we were looking for patients that might be "less severe" or earlier in disease, we wanted to make sure we understood if there was interesting data on how things progressed from this scale. It takes a little bit longer, but it's been validated by different groups. And you can see that this would represent a moderate severe score. Our plasma NfL is listed there, all similar numbers. The other assessment we did was CSF aggregating synuclein and the vast majority of participants had evidence of a profile consistent with MSA and in some cases, PD. Regardless, we found this to be very useful to understand how this assay performed in this population. This is the OHSA that I talked to you about, symptom assessment. This would represent a moderate severity of orthostatic hypotension symptoms. Of note, you will notice that there's a term severe orthostatic hypotension. So for these trials, it's customary to obtain a participant's blood pressure and heart rate in either a supine or seated in a standing position over 1, 3 and 5 minutes, sometimes 10 minutes when they're standing. We did notice that there is an increased proportion of participants that had greater than 30 millimeters of mercury systolic blood pressure drops after 3 minutes in the high-dose group. I think this is important as we interpret some of the data later on. This is a publicly shared data that we're going to talk about later. But just to point you to this graph on the left, the line graph here, you have the gray bar is the placebo scores. These are average scores across groups over 52 weeks. The dark blue is the 50-milligram group. You can see separation at 52 weeks. The 75-milligram is represented in that teal color. We saw early separation at 6 months and then statistically that waned around 52 weeks. But the way I really interpret this data is that there seem to be a benefit for patients treated with both 50 and 75 milligrams to group statistically. We can calculate what's called a treatment effect, and that's the change in -- from 52 weeks to baseline in treated patients minus the change in the placebo divided by the change in placebo to give that percent you can see that treatment effect approaches 50% in 50 milligrams and approaches 30% or almost 1/3 in 75 milligrams. And those differences are numerically are expressed with a 3.8 UMSARS different and 2.4 difference for 75 milligrams. In the context of what has been written and considered as to "what's meaningful" in patients, generally, people think 1.5 points is meaningful. So I think in the context of what has been written, these numbers were quite impressive and quite encouraging as we consider what it means to patients who suffer from this type of a dreadful disease. So the new data that I want to talk about today is what happens when you covary for CSF, NfL. And as Roy said, CSF NfL turns out to be much higher in MSA patients. And there's been some debate in the field as to whether or not NfL could be used as a biomarker of disease progression or does it tell you something about the patient's clinical progression. And to quickly summarize what we see, patients with MSA have high or elevated CSF NfL and that elevation remains sustained across 52 weeks. This agrees with other data that's been published in other groups. But importantly, the higher the baseline NfL, the greater severity of progression clinically over time. And this was important data that we looked at and thought about. We saw the same thing with imaging that I'll talk about in a minute. So when we're interpreting the clinical data, I thought it was important for us to really talk about what -- how CSF NfL affects the results when you enter it as a covariate. And this was predefined in the statistical analysis plan. But you can see when you do this, you see similar results with the 50 milligrams, about a 46% treatment effect, but that high dose group improved substantially to where you're getting about 1/3 treatment effect or about 2.7 UMSARS points difference between placebo. And you can see the comparison to the top line data that I just talked about. So as we talk about some of these data in terms of imaging and biomarkers, I'm now going to start using the covariate CSF NfL to understand more -- a better picture of how these patients are doing over the course of this trial. One of the questions that some of our investigators asked once we disclosed the top line data was, well, have you looked at which items of the UMSARS have improved, certain items have improved more than others? And so what we've done here is give you a forest plot of these individual items. And so on the left, you have 50 milligrams twice a day. On the right, you have the 75 milligram dose. And you can see that light dotted line, 0 and so everything to the left of that line favors treatment, everything to the right favors placebo. And you can see that there's a general improvement across multiple clinical symptoms or less decline, I should say, in treated patients. And that occurs in speech and swallowing, across dexterity, things like cutting food, dressing, hygiene, even to an extent walking. You can see that it's interesting that the fall rate, or the fall severity seems to go up in the 75 milligrams, which is intriguing when you keep a person preserved in their walking, you might actually see that, and I might actually be telling you the drug is doing something. And the signal on orthostatic hypertension, we'll talk about that in a little bit. We saw similar signs in the orthostatic hypertension questionnaire, the OHSA, which is encouraging, thinking that this is not just an isolated finding. So overall, my interpretation of this item analysis is that there is kind of a broad impact of this drug on clinical progression. It's not just 1 or 2 items that are driving it, which is encouraging as you're trying to interpret the totality of the data. So we're are going to focus now on some of the imaging work, and we've been working very hard with Alterity to try and understand some of these patterns. Again, this is the first time that there was a global multicenter study using QSM. So it was quite ambitious, and I applaud Alterity's gumption to take this forward. First, just a reminder of what QSM is. It's a term that we don't use in our vernacular very much, but QSM really is a way that we quantify how much iron is in the brain. In this case, we're looking at certain regions of interest. So what does it measure? It really measures the strength of magnet susceptibility. We know that iron FE2+ is magnetic, paramagnetic. And so you put someone in a magnet, you're able to take information from how those protons move around, electrons move around and get a sense for how much magnetization is there. You're able to use complicated mathematical formulas that basically extract the quantity of that iron in that area. And the interesting part of QSM is that it's not only quantitative but reproducible. So we're able to do this in Italy, in the U.K., in the United States, in Australia and get reliable data to understand, generally speaking, how much iron is in the brains of patients. In terms of MSA, our work was in preparation for this Phase II study really solidified 3 regions that were important for iron. The lentiform nucleus collectively refers to 2 different regions, the putamen and the globus pallidus, and I'll show you a picture of those in a second. That's where we see the most iron, I think, in clinically when you look at scans. The substantia nigra, which is a region that you know about as you've thought about Parkinson's disease, also has elevated iron. And then the cerebellar nucleus of the dentate also has iron elevations. It's also important to notice that there are things that affect QSM readouts. One of the more -- the most biologically meaningful impact is age. So as you get older, you have more iron in the brain. This is very important, especially when you consider a trial that you would need to control for a person's age. So part of the novelty innovation that we took in this trial is to create patient iron maps that account for their age, their sex to create a score that's important to that patient given where they are in their stage of life. Disease burden also affects iron accumulation. There are different ways you can measure disease burden. You can measure it clinically, you can measure it using a biomarker. It turns out NfL also correlates with iron. You see greater correlation, and I'll talk about this in a little bit between iron and NfL in these regions. So when you're doing these analysis, it's important to understand what you're -- how you're doing the analysis and how you're interpreting it. And I show you this picture, as I said to David, if we're going to talk about image, we've got images, we've got to show an image. And so this is kind of what the readout looks like. So on the left, you'll see an image of the substantia nigra. If you can see my cursor, there's a little area deep in the brain. That is the substantia nigra. The red nucleus is right below it, the kind of circular area. But you can see that it's a small region. It can be noisy. And you can imagine doing a global study that small regions that are noisy are sometimes difficult to track over time. On the right, you can see the globus pallidus and the putamen. The putamen's kind of on the outside, globus pallidus is on the inside. Collectively, we talked about this as the lentiform nucleus. And I think these are 2 regions that just show you what the pictures look like. So let's talk about some of the data. The first important question that we wanted to know was we know that iron distinguished MSA from Parkinson's disease and healthy controls and the location of that elevation probably also distinguished MSA from other similar diseases. But how does it move over time? And I've got here some box and whisker plots, which really show how the change of iron over the course of the year trial differs between regions. So that little white line in the middle represents the median change from baseline to 1-year follow-up. You can see the substantia nigra is relatively flat in terms of -- it's not changing a lot. And that could be because of the small size of the region, it could be noise from the different scanners in different locations or even motion. But suffice to say, it didn't turn out to be a robust region that showed iron change. However, the putamen and the globus pallidus, lentiform nucleus turned out to be very interesting. So you can see there's increases over that time that seem to be very informative over the course of the trial. And then the dentate nucleus is generally flat as well. I'll talk about that in a second. And how do dosed groups do compared to placebo groups. And so what I'm showing you here is a forest plot where we've accounted for the participants age, sex, baseline CSF, NfL and baseline iron levels in this model. Everything to the left of the line indicates favoring drug. So you can see that in the 50-milligram dose, we have quite an interesting pattern where there is a favoring of therapy in reducing the amount of accumulation as compared to placebo in key regions of MSA, especially when I look at these data, the globus pallidus turns out, I think, a very important region. In 75-milligram, the differences don't appear as strong than the 50 milligrams. However, when you look at some of the data, the globus pallidus also does turn out to be an area of interest. What was also curious was the dentate nucleus. And it turns out that one of the one of the downstream effectors of glymphatic function, this is the part of -- this is how the brain clears waste ends up being the dentate nucleus. And it is intriguing to us to see that while we were seeing signals of reduced iron in MSA important regions, we saw a signal of dentate of greater iron accumulation. And this would be consistent with what we and others have reported in terms of intact glymphatic function. And so you could hypothesize that what we're seeing is there's excess labile iron that's being trafficked out of important MSA regions and showing up in the dentate nucleus, which is where the downstream glymphatic function works. Hypothesis generating, of course, but it helps us kind of synthesize what we're seeing through the snapshot of this iron imaging. One of the big questions, though, is how does your iron imaging data relate to clinical symptoms. And so this has also been a very fruitful line of research and evidence, I think, of the function of this ATH434 and how it can potentially alter the disease progression and the disease biology of MSA. So what I'm showing you here is the correlation between the change in iron from baseline to 52 to the change in UMSARS score from baseline to week 52. And the strength of the heat of that picture shows you the strength of that correlation. The take-home message is that there is a correlation that is strong between how much iron increases in these regions and how much clinical symptoms worsen. You can see this, especially in these regions like the globus pallidus, the lentiform nucleus that is a very strong correlation between these 2 biomarker and clinical symptom relationships. Now what happens in the dosed patients? We see something very interesting. It's different. In fact, we see an absence of this correlation. So all those significant correlations go away in treated patients. And you can see these numbers are represented here, 50 milligrams and then 75 milligrams. And so we call this as a decoupling. So that coupled relationship of iron and clinical symptoms is now decoupled in treated patients. And this is really helpful in understanding, giving us mechanistic validity to how this drug is affecting patients. I'll show another image to help explain this. So in this image, we've graphed the standardized regression slopes. And you can see in the gray is placebo. And you can see the regression slopes are high, and they're greatest in the lentiform nucleus. And you can see the regression in the treated patients is much lower. And this really indicates that decoupling. And so taking this together, we know that iron is elevated in MSA. We know the regions that it's elevated. We can see that it increases in MSA affected regions over time, and that's linked to clinical worsening and this drug alters that relationship. So this is important data that really gives us a clear signal that this drug is doing what we think it's doing. And I can't talk about imaging without really tipping my cap to some very important work with brain volume, that's really I think, revolutionizing the field and how we conceptualize some of the imaging outcomes in MSA, addressing some of the more difficult problems. And I show these 2 patients here to really illustrate this challenge. The patient on the top, you'll appreciate, has a much smaller pink region than the patient on the bottom. And that is that same lentiform nucleus area. And in certain patients, they'll present with atrophy, selected atrophy of that area. We might call that patient striatonigral degeneration, they might have more Parkinsonian symptoms, MSAP. And to the -- and then the second frame, the sagittal frame, you can see the teal is the cerebellum and the yellow is the brainstem, and that might be more normal. If you look at the bottom patient, they've got generally a good volume of lentiform nucleus, but their cerebellum and brainstem is very atrophied. And this is part of the challenge for MSA is that you can have patients that have different regions that are affected in a different magnitude. And when you're trying to design a trial that looks at an outcome measure that's uniform in these patients, it's going to be a challenge. And one of the works that we've done is develop this what we're calling atrophy index. It takes into account the volume of these different regions compared to the volume distribution of unaffected patients and gives you a value that you can actually track over time. And we call this MSA AI, atrophy index. Of course, this study was not powered to detect the atrophy changes, but the important part is that we see that drug favors the rates of atrophy change over the time, and I've illustrated that here. You can see the placebo declines over time at both 26 and 52 weeks and the rate of that decline has lessened in treated patients. So a tip of the cap to all the people that have done this hard work for this, but also I think -- and I hope you believe as well that this drug is clearly having an effect on the disease pathology in MSA. So in conclusion of this segment, we know that -- I hope I've convinced you that iron accumulates in these MSA-affected regions. We were able to measure this. We see strong correlations between iron accumulation and clinical severity. But in treated patients, this is decoupled. And this decoupling really gives us evidence that ATH434 is interrupting the link between iron accumulation and disease progression. [ With ] that, I thank you, and I'll turn it over to David, who's going to discuss Phase III planning.

Thanks a lot, Daniel. That was a really very interesting overview. And I do want to recognize the work that was done in your lab, both to not only refine and operationalize those neuroimaging methods, but to also implement it in a multicenter trial. So I'm really exciting to see that work. Okay. So I'd like to now talk a little bit about our plans going forward for Phase III. And in particular, I want to talk about dose selection. I think for those of you who saw the data that Dr. Claassen presented, you'll see that we do see robust efficacy at both dose levels, but that there didn't seem to be greater efficacy at the higher dose. And then the question is why. And we're going to talk about that in a moment. But beforehand, it's good to focus on the robust data that we did see at the 50-milligram dose level, where there was up to 48% slowing of disease progression on the MSA rating scale. And that was statistically significant. And I would also point out, as Daniel just showed you that we do see a nice correlation between the change in iron and the change in disease severity, which is really that mechanistic basis for how we're accomplishing that efficacy. But the data -- and we haven't had time to go through this today in the interest of time, but we have shown on several secondary clinical endpoints that the same data we showed UMSARS is also reinforced. So we saw a benefit on the clinical global impression of severity. We saw stabilization of symptoms of orthostatic hypotension that are so important in these patients. We also saw objective evidence of improved mobility as measured by things like step count or total walking time or the number of times an individual sits goes from a sitting to a standing position, things that all are relevant to your daily activities. And then finally, at the 50-milligram dose group, we saw similar rates of adverse events in both 434 treated patients and placebo-treated patients and no serious or severe adverse events. And regarding safety, the same thing was seen at the 75-milligram dose group. So then the question becomes which dose group are we going to take into Phase III. Now just a little bit of background of what we did in Phase II is we did assess the blood levels of 434 so that we could determine what the actual exposure was. And so all the participants in the Phase II trial had samples collected at various time points throughout the trial, not many specimens, but enough specimens that we could use to put into a mathematical model where we could determine the actual exposure over the 12-hour dosing period when they got the drug. And that is shown on the right side. And you can see that what's plotted on the Y-axis is the area under the curve over 12 hours. That's the total exposure at both 50 and 75 milligrams. And as you can see, we do have about 50% higher exposure at the 75-milligram dose level as compared to the 50-milligram dose level, which makes sense because the dose is 50% higher. So that's a very important thing to confirm to make sure that we are actually getting the exposure that we expect. Now we then went on to take these exposures for each individual subject, and then we tried to pair that in a similar way to what Daniel showed regarding the neuroimaging. And what we did was for each trial participant, we would plot their efficacy data based on the modified MSA rating scale or UMSARS versus their exposure. And then we -- if we do that for everybody, irrespective of their dose because sometimes some people in a low dose get a higher exposure and sometimes the converse is true at the high dose, you then plot that efficacy versus concentration curve. And what that shows is that if you have a flat slope that your higher concentrations don't necessarily yield greater efficacy. And that indeed is what we did show in the trial. In fact, what -- I guess the way to view it is that despite the dose proportional increase in that exposure that we observed over the time or over the dosing interval, we did not observe greater efficacy. And another way to view this is that we really observed a plateau of efficacy at the 50-milligram dose group and that there was no incremental benefit of higher exposure. And for that reason, we felt that the efficacy at 50 milligrams was saturated and that there was no benefit to going higher. So based on that, our planned dose selection for Phase III is the 50-milligram dose level given obviously twice a day. And that is supported by the efficacy data that I just reviewed with you, the desirable pharmacokinetics and the relationship between the kinetics and the efficacy and the favorable safety profile. And I would say that another thing from a regulatory standpoint that's always quite important is, in general, you try to give the lowest effective dose. There's always potential side effects associated with drugs. So from a regulatory standpoint, it's always desirable to give the dose that is the lowest that has the least potential for side effects. So I now want to talk a little bit about the Phase III design in a bit more detail. We are planning a single Phase III trial in approximately 200 patients. And as both Dr. Freeman and Dr. Claassen did allude to, there are clinical criteria for making a diagnosis of MSA, but we're also requiring additional criteria to maximize the precision with which we identify these patients. We think that was a large reason for our success in Phase II, and we really plan to continue that going forward in Phase III. So patients will need to be ambulatory without assistance, so they're not too far advanced and they're not too severely impaired. I'm glad that Dr. Claassen reviewed the brain atrophy data because in our next trial, we are planning on using the MRI biomarker of brain atrophy instead of brain iron, mostly because it's easier to operationalize, and it is equally or more reliable for identifying MSA patients. And then as discussed, we are also requiring patients to have elevated plasma NfL to enroll so that we are excluding patients who might be early with disease who have Parkinson's disease. As mentioned, Parkinson's patients have low NfL, MSA patients have elevated NfL, and we are going to use that as a screening criteria as well. Patients will then be randomized in equal numbers to 50 milligrams twice a day or placebo and treated for 12 months. Importantly, as has been discussed, NfL is an important biomarker to kind of predict the rapidity of disease progression at baseline. And as a consequence, we are going to stratify patients based on that. So patients with low NfL will be in one strata, where they'll be randomized to either dose group and then high NfL will be stratified. And this ensures balance between the 2 populations of low and high NfL. The primary endpoint we are proposing to the FDA is the modified UMSARS I as discussed. We think this should be a straightforward discussion, but we definitely need to have that agreement with the agency. And then we will be including various secondary endpoints, the orthostatic hypotension symptoms as previously discussed, wearable movement sensors, where there are other secondary endpoints that we think are important that we will include. Finally, regarding analyzing our efficacy data, given the importance of CSF NfL in terms of its ability to affect or predict disease progression, we will be including this among other covariants in order to analyze the data. And then I should pause and say that this is our concept of what the Phase III study should look like. This is obviously something that we need to reach agreement with the FDA, and this is the proposal that we have put before them. Okay. So to wrap up, I think we're very well positioned for catalysts in 2026. For those of you who follow our news flow regularly, you know that in the last month or so, we've disclosed that we've reached alignment with the FDA at 2 Type C meetings, one related to clinical pharmacology, bioanalytical and nonclinical elements of our program. And then just this week, we disclosed that we have reached agreement with the FDA regarding our chemistry and manufacturing plans regarding how we're going to actually make the drug and release the drug. So that is all very good news. And I will also mention that we are on track for having a so-called end of Phase II meeting mid-year, where we will discuss the Phase III protocol in some detail as well as any other issues that are not -- have not been fully resolved. But that package is in front of the FDA. So we are looking forward to a productive discussion. Following that, an agreement on the trial design, we will be initiating start-up activities by the end of the year, and we aim to dose our first patient within 6 months of receiving written feedback from the FDA. And at the same time, we'll be identifying sites to participate -- excuse me, qualify them for participation and continue manufacturing and patching our drug supply. Finally, over the last several months, we have really been focused on preparing for the future. We're expanding our intellectual property protection with patents surrounding 434 in MSA and other patent activities. We hope to be disclosing new information on this in the near-term. And we do continue to strengthen our organization by building out our teams with the relevant expertise so we can conduct our regulatory interactions as well as our clinical development activities. So I'm going to stop there, and I will turn it back to Tara so that we can address some questions that may be on your mind. So thank you again. And Tara, back to you.

So yes, at this time, we'll be conducting a Q&A session with our 3 speakers. [Operator Instructions] I will now turn it over to PJ Kelleher from LifeSci Advisors to read the questions that came over the webcast.

A couple of questions that have come in, and we'll start and kind of ramble through. But can you talk about how well does UMSARS capture functional decline in patients with MSA? And can you tie in any of that to the questions we've talked about on functional impairment in these patients?

Yes. I'd probably ask as much as possible, I'm going to defer to the clinicians who are experts in this area. So I would ask maybe Roy and Daniel to comment on that.

Do you want to go first, Daniel, and then I will fit in or vice versa?

I always like to listen to you Roy, you go first. Yes.

Yes. So this is a multisystem disease. And without going into too much detail, it's been challenging over the years to find an instrument that measures the complexity of the generation that occurs over time. I think the UMSARS in its current form does a very good job. I think there's variability among patients. And I think it captures that variability very well, measures the decline well. And I think, particularly as David mentioned, with the help of diagnostic biomarkers gets an appropriate homogeneous patient population in the clinical trial. So the short answer is, I think it captures the patient experience very well.

Yes. I just would say that when you talk about -- when you talk to patients about what are the things that really bother them. I think speech, swallowing, gait impairment come up a lot and then dexterity as well. So I think we capture all those things in this scale.

Awesome. Talking MSA. MSA has obviously been a challenging therapeutic area in the past for certain drugs in development. And your -- and this is probably for Roy and Daniel's approach here, but what do you guys think that's different about Alterity's approach that gives them a strong or best chance of success in the Phase III?

I think, Daniel, this is your shot.

Sure. Yes. So I would start off by saying I think Roy mentioned the heterogeneity of patient at presentation. I think we've done really a lot of work in trying to, one, make sure these patients have MSA and use polymarker approach is sort of word we're using, a polymarker approach to not only make sure they have MSA, but also track how the disease progresses over time. And I think in rare diseases, it's really -- it's hard. It's really difficult in rare diseases to see -- rare neurodegenerative diseases to see change over a year. And when I look at this data, I see there's an UMSARS signal. It's supported by wearable sensors. It's supported by clinical global impression of severity that's supported by OHSA measurement. So it's kind of the totality of data that's telling you that there is a signal going on. So I think that encourages me from -- it's a really clear go signal to go into the Phase III. And the other point I'd make is there's been so much interest in the field in reducing synuclein or alpha-synuclein. I think this is a novel mechanism that has a lot of preclinical premise and rigor. This concept of how dysregulated iron can prevent -- change the disease course or alter disease course. It's a different mechanism. And it's not either or it can work in synergy. If there is a synuclein targeted drug that works, this could be working with it. So I think -- but I think the novel mechanism of action also really is -- I appreciate in terms of looking at a very difficult to treat disease in a different way. So I think, yes, a lot of work has got into this, and I think shows a clear signal. And we're taking what we learned from the Phase II and putting it into the Phase III. So all that's good.

I might just -- and Daniel if you wanted to say something, but I wanted to amplify a little bit about the patient selection because I think it contrasts how we're approaching this development with other sponsors. We know that one company that has an antibody that's in development is doing a 360-patient study. We also know that another that has a small molecule in development for MSA that originally had a sample size of 200 patients increased, and this is a Phase II study, increased their sample size to 350 patients, I think, because they may want to increase the power. We've taken a different approach. You can see that we've proposed a Phase III study that is about 200 patients. And that study is very well powered to detect a treatment effect similar to the lower effective dose in Phase II. So it's quite conservative. But as Daniel knows, when we conducted the Phase II study, we were very scrupulous about how we selected patients. Every patient had to have not only clinical criteria that were pretty refined, they had to have neuroimaging and NfL data. And every patient was reviewed before they were given a randomization code and allowed to come in the trial. We think that's the way to succeed with a rare disease that is difficult to diagnose. And I believe we're the only ones that are using neuroimaging for sure. I don't know if the others are using fluid biomarkers to select patients, but I'm not aware that that's the case. So I think that is one important distinction between our development and the other development programs.

Yes. Should I supplement that? I've got 1 or 2. I'll make the points very briefly. If you think of any clinical trial, I think 4 components come into this. One, what are the preclinical data? What are -- if we talk about a Phase III trial, what are the Phase II data, what is the study design and what is the mechanism of action of the drug. And I think Daniel mentioned there is a strong set of preclinical data. I think what is strongly supportive of going forward is that the Phase II data, it doesn't just show efficacy in a single measure, but it is across the board. And I think this is essential in a disease like multiple system atrophy. David spoke in detail about the rigor of the design of the Phase III trial. And then just to make one point, which is an amplification, perhaps a slightly different view to the point made by Daniel. And that is I think we have a number of trials in progress in the past that have looked -- at that have looked downstream in the pathogenesis, looked at the protein that is deposited. In this case, alpha-synuclein targeting that protein. Here, we have an approach that is actually upstream in the earliest stages of the neurodegenerative and the pathogenic process, which I think creates a sense of novelty and excitement and one which I hope will bear fruition.

Awesome. And then one that somewhat ties in is from a clinical perspective, how meaningful is ATH434's effect on UMSARS? And why ultimately did you select UMSARS as the primary endpoint in the Phase III?

Well, I mean, I'll just comment a little bit about the -- part of the reason that we feel the data are exceptional is that both dose groups in the Phase II study demonstrated efficacy above this threshold of 1.5 points on the UMSARS that's been shown independently to be the minimal clinically important difference. So that is -- that's the evidence, if you will, that the drug is actually doing something beneficial as to what is important on a clinical level, that might be a little harder to take away from aggregate data. But individual subject, we can see individual subjects have improvement on single items that can have a big impact on their daily functioning. I guess the one thing I would also add to that is that the effect on UMSARS I, I think Roy pointed this out well. We selected that endpoint, and we've been encouraged by the FDA to use that endpoint in all of our key regulatory interactions in the past at our pre-IND meeting at a Type C meeting we had several years ago before we completed phase -- or before we started Phase II, they recommended us to use UMSARS I. And that's because, as Roy pointed out well, the FDA is very clear they like endpoints about how patients feel, how they function or how they survive. And clearly, UMSARS pertains to the first 2. Down the road, if we're successful in Phase III, we do see there's potential to demonstrate in a different type of trial with -- if we do indeed continue to change the trajectory to impact survival. But UMSARS I definitely affects and measures function and the feelings of patients.

Awesome. That concludes the written in questions. I'll turn it back to Tara at this point.

Great. David, any closing remarks before we wrap?

Yes. I just want to thank everyone for participating. I really want to thank Roy and Daniel for their excellent presentations and their clinical perspective on the disease and on the data and on the path forward. We're really excited about where we're at in April of 2026, and we're looking forward to a productive meeting with the FDA mid-year, and we hope to really advance to Phase III quickly because these patients and their families really need a therapy. So thank you again for attending, and we appreciate your support.