Welcome to the Alterity Therapeutics Virtual KOL event. At this time, all attendees are in a listen only mode, and a question answer session will follow the formal presentation. 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. Thank you very much for joining this call. We're really excited about the progress we've made on ATH434 for multiple system atrophy. We're really fortunate today to have two clinical experts joining me to help put this disease in perspective, 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 investment. Oh, sorry, we skipped past those. I encourage you to review these as well as information on our website. As mentioned, joining me today is Roy Freeman, who's 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. 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, starting with our natural history study, and has been instrumental in both the clinical aspects of our program as well as the neuroimaging. I think you'll get an opportunity to hear about some very exciting data regarding the phase II study from Dr. Claassen.
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. 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. We'll give a brief overview and update on where we have gone in the recent past with discussions with the FDA. 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. 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. 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. I'll tell you more about the attributes of the drug itself. Finally, based on our phase II results and our recent interactions with the FDA and our upcoming interaction with them on mid-year regarding the phase III program, we expect to be advancing rapidly to phase III in the near term. Before I talk about how ATH434 works, I just wanna set the stage a little bit about the pathology of this disease. There are two key aspects that we target. One is alpha-synuclein.
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. 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 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. In the central nervous system, iron is very important for synthesis of neurotransmitters like dopamine. 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. 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. What you see in the slide are patients in blue with age-matched controls in gray. We see that in the areas of pathology, there is iron accumulation compared to patients of a similar age. 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. 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. This is a tool that we can use to actually measure the iron in the brains of patients, of living patients. 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. To try and put this in perspective, as mentioned, for a variety of reasons, there is abnormal control or disrupted control of iron in the central nervous system that leads to excess amounts of the so-called reactive iron or Fe2+.
Normally that's handled by these endogenous iron chaperones called PCBPs. That's, I know, a bit of a mouthful. When there is excess amounts of iron and excess labile iron, it actually drives pathology. You can see along the top path that excess iron can actually promote alpha-synuclein to aggregate. Those aggregates of alpha-synuclein can actually damage intracellular structures like DNA or mitochondria. 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. In doing so, while they preserve the neurons, they too become overloaded with that aggregated synuclein, and they are impaired, and they can't myelinate the neurons properly, which ultimately contributes to impaired neural transmission. That's one pathway of damage caused by the excess iron. The other pathway is that iron itself is the source for free radicals.
The excess iron generates free radicals that do two things. Number one, they also promote the alpha-synuclein to aggregate. They also can damage the intracellular structures that I talked about, mitochondria, and cause lipid peroxidation in a process that's referred to as ferroptosis that ultimately leads to cell damage and cell death. What we're really trying to do is to target this iron in the disease.
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. Then when alpha-synuclein aggregates, 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. What we're really trying to do is break this cycle. 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. We've shown this nicely in multiple animal models of MSA. In doing so, that will preserve neurons and their support cells with the ultimate goal of stabilizing function or slowing its decline. 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.
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. 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. 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.
It really does have a broad treatment potential. Finally, the drug does have orphan drug designation in the United States as well as in Europe. 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. I will stop there, and then I'm pleased to turn it over to Dr. Freeman, who's gonna educate you a bit on multiple system atrophy. Dr. Freeman.
Thank you. Thank you, David. Thank you everybody for listening in anticipation. I'm going to give an overview of MSA, 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, that is the underlying point that I think you should carry with you throughout this presentation. 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. Affecting mobility, gait, coordination, and also the automatic functions. 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. Those all should be taken into account when a patient with possibly multiple system atrophy presents. 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 U.S. 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 six and 10 years. David gave you a beautiful overview of the biology of synuclein. Multiple system atrophy is one of the 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.
These four are all proteinopathies, and they are characterized by the deposition of misfolded alpha-synuclein. 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. The oligodendrocyte is one of the family of neuroglial cells. This is in contrast to the pathological hallmark in Parkinson's disease, which is the Lewy body. 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 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. We published a critique of those diagnostic criteria. In 2022, which I call these the new diagnostic criteria, they're not that new anymore, we published new diagnostic criteria for this disease. These are the following. We divided the disease into four category. Obviously, the gold standard, neuropathologically established disease.
But from the clinical standpoint, two categories, clinically established, which is highly specific, and clinically probable, which is less specific, but has greater sensitivity. 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 or 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.
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. I won't go into them in this lecture, should you wish, that article on the previous slide is available to read. Let's talk a little bit about the clinical course. I mentioned the diagnostic criteria. I think what we know with this disease is it moves along, it moves along aggressively and relentlessly.
It goes from the premotor symptoms, those are incorporated in the possible prodromal category, a urinary dysfunction, a disorder of sleep in which people act out their dreams, REM sleep behavior disorder, and low blood pressure upon standing, orthostatic hypotension. 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 six 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? 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 four 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. 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 four, 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 the activities, 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. More recently, wearable digital outcomes, which provide a more objective measure of function. I want to talk briefly about biomarkers, we divide biomarkers into several groups. Most relevant for this study is the diagnostic biomarker, we also use biomarkers to prognosticate, to predict, and also to measure response, a pharmacodynamic biomarker, a measure of target engagement.
The biomarkers most likely widely used are imaging, more to come on that, seed amplification of alpha-synuclein, immunohistochemical detection of cutaneous deposition of phosphorylates 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. I want to tell you a little about this and allay some misconceptions and simultaneously introduce the concepts that underlie this biomarker. You can see that in the figure at the bottom on the left. It's expressed in long myelinated axons. These are the fast conducting axons, those are the axons that are myelinated and are found in the white matter tract. This supports the stability of the axon. When there is damage degeneration, neurofilament is released into the cerebrospinal fluid and into the blood.
As you see in the middle of that figure, damage releasing neurofilaments, those little blue 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. This occurs across diseases from multiple system atrophy, to multiple system atrophy to multiple sclerosis. It is higher in multiple system atrophy than it is in Parkinson's disease, 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 four years of the disease, it is high in the beginning, but remains at that same high level. Not a surrogate marker for disease progression. Needless to say, lots more to talk about. Happy to answer any questions, but I think I've 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. I first just wanna remind people the design of the 201 study. As you know, this was a randomized double-blind placebo-controlled study, and participants were randomized into either receiving 75 mg, 50 mg twice a day, or a 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 gonna go over with you today worked or early in disease. We learned a lot about iron, how to measure it. We learned a lot about things like NFL, the clinical assessments that we use. On that left side, you can see that we had 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 four years.
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. We also think that the drug would putatively help patients that were, quote-unquote, early in disease or with less severe impairment. The other novelties to the study is that we required participants to have elevated brain iron on MRI. I'll talk about that recently. We just got a paper accepted today, which goes through that methodology, and that was an important inclusion criteria.
We required participants to have elevated plasma NFL, and this was helpful to increase the positive predictive value that participants actually had MSA. All that to say, these participants were 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 'cause 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 hypotension scale, which really measures 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 gonna talk to you a little bit more about some of the learnings from this, we did for the first time in a global study, employ QSM imaging, iron imaging in clinical MSA. This was also a tremendous accomplishment and learned a lot from this trial. 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. These are things that are important to participants' function in MSA. Of course, speech, swallowing are clearly important in terms of bulbar, or, you know, mouth, and swallowing function that gets affected in MSA.
Think about things that require dexterity, handwriting, cutting food, dressing, hygiene. All are 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. These are interviews between the clinician and the patient and caregiver, and then they are rated based on the severity zero meaning no severity, up to four meaning maximal severity. The higher the score of these total numbers, the worse the severity. Importantly, it's notable that this is a validated rating scale.
Validated and also accepted by the FDA as a clinical import point to support treatment of MSA. 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 two and a half 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 parkinsonism-plus scale, which is a clinical exam, and the higher their score on this, the more evidence of clinical disease. 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.
We thought, given the fact that we were looking for patients that might be, quote-unquote, 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, it's been validated by different groups. 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, the symptom assessment. This would represent a moderate severity of OH, orthostatic hypotension symptoms. Of note, you will notice that there's a term severe orthostatic hypotension. For these trials, it's customary to obtain a participant's blood pressure and heart rate in either a supine, a seated, and a standing position over one, three, and five minutes, sometimes 10 minutes when they're standing.
We did notice that there was an increased proportion of participants that had greater than 30 millimeters of mercury systolic blood pressure drops after three minutes in the high-dose group. I think this is important as we interpret some of the data later on. This is the publicly shared data that we're gonna talk about later. Just to orient 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 mg group. You can see, separation at 52 weeks. Excuse me. The 75 mg is represented in that teal color. We saw early separation at six months, and then statistically that waned at around 52 weeks. The way, I really interpret this data is that there seemed to be a benefit for patients treated with, both 50 mg and 75 mg dosaged groups. Statistically, we can calculate what's called a treatment effect, and that's the change 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 mg and approaches 30, almost a 1/3, in 75 mg. Those differences numerically are expressed with a 3.8 UMSARS different and 2.4 difference for 75 mg. In the context of what has been written and considered as to begin quotes, "what's meaningful," end quotes, in patients, you know, generally people think 1.5 points is meaningful. 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 dreadful disease.
The new data that I wanna talk about today is what happens when you covary for CSF-NFL. As Roy said, CSF-NFL turns out to be much higher in MSA patients. 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. To quickly summarize what we see, patients with MSA have high or elevated CSF-NFL, and that elevation remains sustained across the 52 weeks. This agrees with other data that's been published in other groups.
Importantly, the higher the baseline NFL, the greater severity of progression clinically over time. 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. When we're interpreting the clinical data, I thought it was important for us to really talk about how CSF-NFL affects the results when you enter it as a covariate. This was predefined in the statistical analysis plan. You can see when you do this, you see similar results with the 50 mg, about 46% treatment effect.
That high dose group improved substantially to where you're getting about a 1/3 treatment effect or about 2.7 UMSARS points difference between placebo. You can see the comparison to the top line data that I just talked about. As we talk about some of these data in terms of imaging and biomarkers, I'm now gonna 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?
Are there certain items have improved more than others?" What we've done here is give you a forest plot of these individual items. On the left, you have 50 mg twice a day. On the right, you have the 75 mg dose. You can see that light dotted line zero. Everything to the left of that line favors treatment, everything to the right favors placebo. You can see that there's a general improvement across multiple clinical symptoms, or less decline, I should say, in treated patients. 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 75 mg, which is intriguing. When you keep a person preserved and they're walking, you might actually see that, then I might actually be telling you the drug is doing something. The signal on orthostatic hypotension, we'll talk about that in a little bit. We saw similar signs in the orthostatic hypotension questionnaire, the OHSA, which is encouraging, thinking that this is not just an isolated finding. Overall, my interpretation of this item analysis is that there's kind of a broad impact of this drug on clinical progression.
It's not just one or two items that are driving it, which is encouraging as you're trying to interpret the totality of the data. We're gonna 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 multi-center study using QSM, 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. What does it measure? It really measures the strength of magnet susceptibility. You'll know that iron, Fe2+, is magnetic, paramagnetic. 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.
The interesting part of QSM is that it's not only quantitative, but reproducible. 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 three regions that were important for iron. The lentiform nucleus collectively refers to two 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, 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. 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 most biologically meaningful impact is age. 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.
What 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. 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.
When you're doing these analysis, it's important to understand how you're doing the analysis and how you're interpreting it. I show this picture, as I said to David, if we're gonna talk about image, we've got images, we've gotta show an image. This is kind of what the readout looks like. On the left, you'll see, excuse me, an image of the substantia nigra. If you can see my cursor, that 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.
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 talk about this as the lentiform nucleus. I think these are two regions that just show you, well, what the pictures look like. Let's talk about some of the data. The first important question that we wanted to know.
We knew 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. How does it move over time? 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. That little white line in the middle represents the median change or, from baseline to one 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 and different locations or even motion. 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. You can see there's increases over that time that seemed to be very informative over the course of the trial. The dentate nucleus is generally flat as well. I'll talk about that in a second. How do dosed groups do compared to placebo groups?
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. You can see that in the 50 mg dose, we have quite an interesting pattern where there's a favoring of therapy in reducing the amount of accumulation as compared to placebo in key regions of MSA, especially when I look at this data, the globus pallidus turns out, I think, a very important region. In 75 mg, the differences don't appear as strong than the 50 mg.
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 downstream effectors of glymphatic function, this is how the brain clears waste, ends up being the dentate nucleus. It was intriguing to us to see that while we were seeing signals of reduced iron in MSA important regions, we saw a signal at dentate of greater iron accumulation, and this would be consistent with what we and others have reported in terms of intact glymphatic function.
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 kinda 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?
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. 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. The strength of the heat of that picture shows you the strength of that correlation. The take-home message is that there's 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 has a very strong correlation between these two biomarker and clinical symptom relationships. Now, what happens in the dosed patients? We see something very interesting that's different. In fact, we see an absence of this correlation. All those significant correlations go away in treated patients. You can see these numbers are represented here, 50 mg and then 75 mg. We call this as a decoupling. That coupled relationship of iron and clinical symptoms is now decoupled in treated patients.
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. In this image, I've graphed the standardized regression slopes. 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. You can see the regression in the treated patients is much lower, and this really indicates that decoupling. 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. This is important data that really gives us a clear signal that this drug is doing what we think it's doing. 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 in how we conceptualize some of the imaging outcomes in MSA, addressing some of the more difficult problems.
I show these two 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. That is that same lentiform nucleus area. 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, MSA-P. In 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.
You look at the bottom patient, they've got a generally good volume of the lentiform nucleus, but their cerebellum and brainstem is very atrophied. 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. When you're trying to design a trial that looks at an outcome measure that's uniform in these patients, it's gonna be a challenge. 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. Then 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 is lessened in treated patients.
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. 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. In treated patients, this is decoupled. This decoupling really gives us evidence that ATH434 is interrupting the link between iron accumulation and disease progression. For that, I thank you, and I'll turn it over to David, who's gonna discuss phase III planning.
Thanks a lot, Daniel. That was a really very interesting overview. I do wanna recognize the work that was done in your lab both to not only refine and operationalize those neural imaging methods, but to also implement it in a multicenter trial. Really exciting to see that work. Okay. I'd like to now talk a little bit about our plans going forward for phase III. In particular, I wanna 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.
The question is why, and we're gonna talk about that in a moment. Beforehand, it's good to focus on, you know, the robust data that we did see at the 50 mg dose level, where there was up to 48% slowing of disease progression on the MSA rating scale, and that was statistically significant. 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.
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 that we showed on UMSARS is also reinforced. 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 goes from a sitting to a standing position, things that all are relevant to your daily activities.
Finally, at the 50 mg dose group, we saw similar rates of adverse events in both ATH434 treated patients and placebo-treated patients, and no serious or severe adverse events. Regarding safety, the same thing was seen at the 75 mg dose group. 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 ATH434 so that we could determine what the actual exposure was. 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. That is shown on the right side. 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 mg and 75 mg. As you can see, we do have about 50% higher exposure at the 75 mg dose level as compared to the 50 mg dose level, which makes sense because the dose is 50% higher.
That's a very important thing to confirm to make sure that we are actually getting the exposure that we expect. 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. What we did was for each trial participant, we would plot their efficacy data based on the modified UMSARS versus their exposure. 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. What that shows is that if you have a flat slope, that your higher concentrations don't necessarily yield greater efficacy. That indeed is, well, what we did show in the trial. In fact, what, you know, 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. Another way to view this is that we really observed a plateau of efficacy at the 50 mg dose group, and that there was no incremental benefit of higher exposure.
For that reason, we felt that the efficacy at 50 mg was saturated, and that there was no benefit to going higher. Based on that, our planned dose selection for phase III is the 50 mg dose level, given obviously twice a day. 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. 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, you know, always potential side effects associated with drugs. From a regulatory standpoint, it's always desirable to give the dose that is the lowest that has the least potential for side effects. I now wanna 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. As both Dr. Freeman and Dr. Claassen did allude to, there are clinical criteria for making a diagnosis of MSA. 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. 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.
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. We are going to use that as a screening criteria as well. Patients will be randomized in equal numbers to 50 mg 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.
As a consequence, we are going to stratify patients based on that. 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. This ensures balance between the two populations of low and high NFL. The primary endpoint we are proposing to the FDA is the modified UMSARS-I is discussed. We think this should be a straightforward discussion, but we definitely need to have that agreement with the agency.
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 a disease progression, we will be including this among other covariates in order to analyze the data. 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. 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 two Type C meetings, one related to clinical pharmacology, bioanalytical, and non-clinical elements of our program.
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. That is all very good news. I will also mention that we are on track for having a so-called end of phase II meeting midyear, where we will discuss the phase III protocol in some detail, as well as any other, you know, issues that have not been fully resolved. That package is in front of the FDA, so we are looking forward to a productive discussion.
Following that, and agreement on the trial design, we will be initiating startup activities by the end of the year. We aim to dose our first patient within six months of receiving written feedback from the FDA. At the same time, we'll be identifying sites to qualify them for participation, and continue manufacturing and packaging 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 and MSA, and other patent activities.
We hope to be disclosing new information on this in the near term. We do continue to strengthen our organization by building out our teams with the relevant expertise so that we can conduct our regulatory interactions as well as our clinical development activities. I'm gonna stop there, and I will turn it back to Tara, so that we can address some questions that may be on your mind. Thank you again. Tara, back to you.
Great. Thank you, David. Yes, at this time, we'll be conducting a Q and A session with our three speakers. To ask a question, please use the written text box at the bottom of the webcast player. I will now turn it over to PJ Kelleher from LifeSci Advisors to read the questions that came over the webcast.
Thanks Tara, and thanks David, Daniel, and Roy. A couple questions have come in and we'll start and kind of ramble through. Can you talk about how well does UMSARS capture functional decline in patients with MSA? Can you know, tie in any of that to the questions we've talked about on functional impairment in these patients?
Yeah. I would probably ask, as much as possible, I'm gonna defer to the clinicians, who are experts in this area. I would ask maybe Roy and Daniel to comment on that.
Do you wanna go first, Daniel, and then I'll fill in or vice versa?
I always like to listen to you, Roy. You go first. Yeah.
Yeah. You know, this is a multi-system disease. You know, without going into too much detail, it's been challenging over the years to find an instrument that measures the complexity of degeneration 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 a clinical trial. The short answer is I think it captures the patient experience very well.
Yeah. I just would say that when you talked about, when you talk to patients about what are the things that really bother them, you know, I think speech, swallowing, gait impairment come up a lot, and then dexterity as well. I think we capture all those things in this scale.
Awesome. Thank you both. Talking MSA's obviously been a challenging therapeutic area in the past for certain drugs and development. You know, this is probably for Roy Freeman and Daniel Claassen's approach here. What do you guys think that's different about Alterity's approach that gives them a strong or a best chance of success in the phase III?
I think, Daniel, this is your chance to go first.
Sure. Yeah. I would start off by saying I think Roy mentioned the heterogeneity of patient at presentation. I think we've done a really a lot of work in trying to, one, make sure these patients have MSA and use a polymarker approach is what word we're using. A polymarker approach to not only make sure, you know, they have MSA, but also track how the disease progresses over time. I think, you know, in rare diseases it's really hard. It's really difficult in rare diseases to see rare neurodegenerative diseases to see change over a year. When I look at this data, you know, I see there's an UMSARS signal.
It's supported by wearable sensors. It's supported by clinical impression of severity. That's supported by OHSA measurements. It's kind of the totality of data is telling you that there's a signal going on. I think that encourages me from, you know, it's a really clear go signal to go into the phase III. The other point I'd make is, you know, 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 disregulated iron can change the disease course or alter disease course.
It's a different mechanism, it's not either/or it can work in synergy. You know, if there is a synuclein targeted drug that works, this could be working with it. I think, but I think the novel mechanism action also really is, I appreciate in terms of looking at a very difficult to treat disease in a different way. I think, yeah, a lot of work has got into this. I think shows a clear signal and we're taking what we learned from the phase II and putting it into the phase III, all that's good.
I don't know, Roy, if you wanted to say something. 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, you know, 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, you know, 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. That study is very well powered to detect a treatment effect, similar to the, you know, the lower effective dose in phase II. It's, it's quite conservative. 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, you know, neuroimaging and NFL data. 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. I believe we're the only ones that are using neuroimaging for sure. I don't know if the others, if the others are using biofluid biomarkers to select patients, but I'm not aware that that's the case. I think that is one important distinction between our development and the other development programs.
Yeah. Should I supplement a little? I've got one or two. I'll make the points very briefly. If you think of any clinical trial, I think four components come into this. One, what are the preclinical data? If we talk about a phase III trial, what are the phase II data? What is the study design, what is the mechanism of action of the drug? 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. 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. Then just to make one point, which is an amplification, perhaps a slightly different view, to the point made by Daniel. That is, I think we have a number of trials in progress in the past 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. 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?
You know, I mean, I'll just comment a little bit about the part of the reason that we, you know, feel the data are exceptional is that both those 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, a minimal clinically important difference. That is, you know, 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, you know, to take away from aggregate data.
You know, 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.
That's because, as Roy pointed out well, the FDA is very clear they like endpoints about how patients feel, how they function, or, you know, or how they survive. Clearly UMSARS pertains to the first two. Down the road, if we're successful in phase III, you know, 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. 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?
I just wanna thank everyone for participating. I'd really wanna 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 midyear. We hope to really advance to phase III quickly because these patients and their families really need a therapy. Thank you again for attending and we appreciate your support.