Everyone, welcome to the 46th Canaccord Annual Boston Growth Conference. We are very excited to have Dr. David Stamler from Alterity Therapeutics. Alterity is dual-listed on both the ASX and Nasdaq. It is roughly a US $80 million market cap company. They have just completed a phase II trial in multiple system atrophy, planning to commence a phase III later this year. David, thank you.
Good afternoon, and thank you for coming to hear our story. These are our forward-looking statements. Alterity actually is an English word that means the state of being different, which really embodies what we are trying to do with our therapy, which is to really change the state of patients with these diseases that we are targeting.
What I hope to tell you about today is about, I think, a compelling opportunity with our lead drug called ATH434, which is a small molecule drug to treat a disease called multiple system atrophy. You have probably never heard of this disease, but by the end of the presentation, I think you will not forget it. We showed in our phase II study that we released last year, that we demonstrated upwards of 50% slowing of disease progression for this disease on an endpoint that the FDA recognizes as important to support a drug approval.
This is a rare disease that affects between 20,000 and 50,000 patients in the U.S., and there is nothing approved to treat it. You can imagine there is a significant commercial opportunity as well as a tremendous unmet medical need. Our drug has a unique mechanism of action that I will spend some time telling you about. It is an oral iron chaperone that addresses the iron accumulation that drives the pathology in these diseases.
Then finally, we have had a series of successful interactions with the FDA over the course of the last 6 months that culminated in a positive end-of-phase II meeting that we held in June, and we are now really actively preparing for phase III. ATH434 is the molecule. I will tell you more about that in a moment. We have been evaluating this for use in several potential indications.
The one that we will be focusing mostly on is called multiple system atrophy, or MSA for short. Those are the three lines you see. We are preparing actively for phase III. The third line on the chart is a unique aspect of the development program, where we did what is called a natural history study, which is a trial with no investigational therapy that just helps us understand the disease.
This is really important for helping us to design and de-risk our phase II program. More on that later. Also, the drug has significant potential to address Parkinson's disease, because there is very similar pathology between Parkinson's disease and MSA, and we will talk more about that in a moment. Multiple system atrophy, or MSA, as mentioned, it is a Parkinsonian disorder.
But the other side of the coin is that it is a very aggressive disease, much more like ALS. So it could be considered a bit of a misnomer to say it's a Parkinsonian disorder. Nonetheless, patients you can see in that diagram on the right side of the slide, present with non-specific symptoms such as sleep disturbance or urinary problems. And it's not until they start developing motor symptoms, whether it's the Parkinsonism that you've probably seen in friends or family members, or the unsteady gait that leads to frequent falls, that they come to the attention of a neurologist. After that, unfortunately, the disease does progress quite rapidly. Patients then require a cane or a walker within a couple of years. And then more than 50% of individuals do require a wheelchair within five years of symptom onset. So it really is a very aggressive disease.
Now, before I tell you about how our drug works, I think it's useful to tell you a little bit about the pathology that we are addressing with our treatment. So in health, there's a protein called alpha-synuclein that is important. It's present in all neurons, and it's necessary for neurons to communicate with one another. However, in diseases like MSA or Parkinson's disease, the protein actually aggregates, and when it aggregates, the body tries to clear it. It generates an inflammatory response, but also the protein can't function, and that underlies many of the symptoms that patients experience. Now, iron is also important in the central nervous system. You probably know iron's role is important in energy production or oxygen transport in the blood.
But in the central nervous system, iron is critical for synthesizing neurotransmitters like dopamine, but also for synthesizing myelin, which is the fatty sheath that wraps around neurons and allows rapid neural transmission. In diseases like MSA and Parkinson's disease, iron accumulates, and once the iron accumulates there, it contributes and drives the pathology. This is a study, an autopsy study, that came out of the U.K., and they actually looked at brains from individuals who died from either Parkinson's disease on the left or MSA on the right, and the patients are in blue. And what you see is that there is actually iron accumulation in the areas of pathology. Now, these are people who died from these diseases, so these are more of a tombstone, if you will, of iron accumulation.
But what we're really trying to do with our therapy is to prevent this iron from accumulating, or if it is there, we're trying to mitigate the damage that the iron actually causes. The question is, how does iron actually drive the pathology? And that's summarized here. As mentioned, iron accumulates at the site of pathology. You get excess labile iron. That's the lighter blue color that you see, and that is present in small quantities. Think of it kind of as a nuclear fuel in a nuclear reactor. You need small amounts of it, but in large quantities, it causes damage. What it does is, it actually causes that alpha-synuclein protein I told you about to aggregate.
That aggregated protein actually is toxic to neurons, it is also toxic to the support cells, the so-called glial support cells, that scavenge it from the neurons so that it does not kill the neurons. But then those support cells become impaired, they cannot provide nourishment and support to the neurons themselves. On the lower panel, you will also see that that iron causes generation of free radicals. Those free radicals themselves cause the protein to aggregate, they are also toxic to cellular structures like mitochondria. What we are really trying to do is we are trying to reduce the pathology caused by that excess iron.
This is a basic science slide I will not focus on in too much detail, but the take-home message is on the right side, where you see that our basic scientists have shown that ATH434 can actually chaperone or redistribute excess iron in three different ways. It can efflux it from the cell, it can increase its storage in a protein called ferritin, it can also buffer it inside the cell. I think what is important, I will ask you to remember this, is that only that first mechanism, the efflux, really leads to a change in iron signal on MRI. To tie this all together, what we see is that we chaperone excess iron in the central nervous system. We reduce the sources of pathology, preserve the neurons with the overall goal of stabilizing or slowing function decline, functional decline. Okay.
This is the molecule pictured on the right side of the slide, binding iron. As I think I mentioned, it is an orally administered drug. We have shown that it actually crosses the blood-brain barrier nicely, which is critical for CNS drugs. Also, it penetrates cells, so it can address the pathology that is going on inside the cell. We have talked about the fact that it binds iron, but it binds it with moderate affinity, so it can move it around the cell. It does not bind it and remove it and cause toxicity. Finally, from a regulatory standpoint, this is an orphan drug, given that there are fewer than 50,000 patients in the U.S. that have the disease. So it is an orphan drug both in the U.S. and in Europe, as well as we do have Fast Track designation in the U.S. All right.
I do not want to focus too much on this slide, except these two rows in the middle, or sorry, the second and third data rows. The second MSA study and the first Parkinson's disease study were the first animal studies that showed us that we could actually achieve efficacy without lowering iron. This does become important when you think about some of the neuroimaging data that I will show you in a moment. All right. Now let us turn to the clinical development program. As mentioned, on the left side of the slide, the natural history study was a study we did several years before we conducted phase II. This is important because we aimed to identify biomarkers to improve the accuracy of diagnosing MSA. It is a clinically diagnosed disease, so these biomarkers are important to improve the specificity of diagnosis.
I will tell you about the phase II program after that. The natural history study, I think the important takeaway is that when we enrolled patients, about 20 patients who met clinical criteria for MSA, then we studied them with extensive testing, lumbar puncture, MRI, et cetera. If you see on the far left side of the slide, at the tip of the red arrow, that dark red staining material is the increased iron that you would see in an MSA patient, you will not see in a Parkinson's disease patient. The center panel is probably the most important takeaway from the study in that we enrolled 21 patients that we thought all had MSA, but it turned out that five actually had Parkinson's disease, as you can see from that assay of alpha-synuclein aggregation.
The reason this is important is we learned this before we did the phase II study so that we could adjust the selection criteria and exclude those people who looked like they had MSA but turned out to have Parkinson's disease. The other part of the study that is important is that our colleagues at Vanderbilt University Medical Center really were able to develop and operationalize sophisticated measures for measuring brain volume on the left. If you see in the green circle area are the brain structures that we are interested in, as well as brain iron in the center panel. Then they really operationalized those so they could be implemented in the phase II study.
This is an outline of the phase II study, where we enrolled 77 patients who met clinical criteria for MSA, and they had elevated brain iron on MRI, as well as elevation of another biomarker called NfL that is elevated in MSA but not in Parkinson's disease. Then patients were randomized equally to those three dose groups, 75 or 50 milligrams twice a day or matching placebo. Then they were treated for 12 months, and we assessed the endpoints that you see listed there on the right. I will outline those on the next slide. The most important clinical endpoint is called the MSA Rating Scale or the Unified Multiple System Atrophy Rating Scale, UMSARS for short, which assesses these domains that are impacted in MSA.
You can imagine with impairment in speech, swallowing, fine motor skills, along with walking and falling, these are symptoms that cause a tremendous amount of impairment in these patients. Importantly, this endpoint is recognized by the FDA as one that will support an approval for this indication. It is something we have already agreed with on the FDA as our primary endpoint. These are the baseline characteristics of the population studied. I will not go through this in detail, but safe to say that the groups were well-matched in terms of most characteristics. The one characteristic I want to bring your attention to, where there was an imbalance, was the incidence of severe orthostatic hypotension. This is the drop in blood pressure that we all experience when you go from a sitting to a standing position.
If you have an intact nervous system, your blood pressure corrects automatically, and you do not notice it unless you are perhaps dehydrated. In this case, by chance, we saw that up to 30% of patients in the high-dose group had a severe drop in blood pressure after standing up for three minutes. This is important because it is a predictor of rapid disease progression in this disease. This next slide is the key clinical endpoint for the study, the MSA rating scale. It is a bit of a busy slide, but on the y-axis is the scale itself. Higher scores are worse.
We see that the placebo in gray deteriorated by about eight points over the course of a year, whereas the two active dose groups, 50 and 75 in blue and teal, they declined by anywhere from 34%-46% less, which equates to a difference of about 2.7-3.7 points. What is important about this is that both dose levels exceed the minimal clinically important difference of 1.5 points. You may notice that the treatment response was bigger in the 50 milligram dose group, and we think a large part of the reason for the fact is that greater rate of severe orthostatic hypotension at baseline played an important factor. When you do actually correct for that baseline imbalance, the treatment effect at 75 milligrams increases substantially.
We have also done population PK analyses in phase II, and showed that we do see a saturation of effect at 50 milligrams. So we do plan on taking the 50 milligram dose group forward to phase III. This is just an item analysis that shows that between the two dose groups, even though 50 milligrams was more effective, we see a very similar pattern of efficacy, which really supports the strength of the finding in both dose groups. This is the orthostatic hypotension symptom assessment. You recall this is a very important symptom that restricts people's abilities to be mobile. Higher scores in this scale are worse. We see that the patients who received placebo in gray deteriorated by about six points, whereas the two active dose groups were stable over the same period of time.
This is a very important finding, and importantly, we did not see greater use of drugs to manage orthostatic hypotension in the active treated patients. It was more common in the placebo patients. This is another patient-reported outcome, Swallowing Disturbance Questionnaire. Again, this is an important component of morbidity and mortality in these patients from either choking or aspirating when they sleep. This is rated on a scale. You see the 15 questions there. Higher scores are worse, so the placebo-treated patients declined by about eight to nine points over the course of a year, whereas the patients receiving active treatment declined by substantially less, with the difference at 50 milligrams being statistically significant. This is the Clinical Global Impression of Severity. The FDA likes these scales as secondary endpoints. This reflects the clinician's overall gestalt to the patient. Again, higher scores are worse.
We see the placebo patients decline the most, with 50 milligram patients having a statistically significantly lower decline, then 75 in between. We do see all the clinical endpoints do really appear to be lining up consistently. This last efficacy endpoint I will mention is the activity in the outpatient setting assessed with wearable sensors that you see pictured on the right lower hand part of the slide, where you see on these items, lower scores are worse. You see if you take step count or total walking time, total walking time patients might decline by about 28 minutes over the course of a day, per day, over the course of a year, whereas those receiving active treatment declined by about half that. This is nice because it is an objective criteria that demonstrates that patients have improved mobility with treatment.
From an adverse event perspective, there is really not a lot to report. We do see similar rates of adverse events in ATH434-treated patients compared to placebo. Importantly, we saw no severe or serious adverse events that were attributed to the study drug, and we saw no hematologic side effects. Okay, so now I am going to briefly touch on neuroimaging in the last few minutes. We like to say you cannot really discuss neuroimaging data without showing a neuroimage. I want to show you that neuroimage now. On the left is a Parkinson's patient. You can see the dark red staining material, the warm color, that does correspond to increased iron. On the right side, this is a different level, the putamen and the globus pallidus. The warm colors do correspond to increased iron. That is really what we are trying to measure.
This is the change in iron in the placebo-treated patients. What you see is Oh, excuse me. Is that back one? Can I go back one? Okay. Oh, thank you. In the placebo-treated patients, over the course of 12 months, we see elevated iron. This is the median value, is increased in the putamen, the globus pallidus, and the lentiform. We couldn't see it in the substantia nigra, because partly it is a smaller region and there is more operational complexity to do that. Nonetheless, we did see increases over time in the placebo-treated patients. This is a comparison of the change in iron that we see in the active treated patients compared to placebo. To the left of the line, a vertical line for each dose group, shows that there is less iron accumulation compared to placebo.
What you do see on the 50 milligram dose group is that there are trends in reduced iron accumulation in these regions compared to placebo. There seems to be a redistribution to this other region in the cerebellum called the dentate nucleus. We do not see that in the 75 milligram patients. The question is, well, how do we know that the iron redistribution that we are targeting is actually having a beneficial effect on the patients? What we tried to do is, we looked at a correlation between the change in iron on MRI and the change in disease severity as reflected by the UMSARS score. Again, higher scores are worse. A stronger correlation is a higher number, and it is also a stronger color on this heat map.
We see in the placebo-treated patients that we have a strong correlation between the increase in iron and the worsening on the clinical score. However, when you look at the active-treated patients, we see that those correlations are substantially reduced. What's happening there, if you think back on the mechanism of action slide, is that in many of these cells, we are actually redistributing the iron within the cell, so it can be still present, but it's not causing the damage. What we think we're really doing is decoupling the iron accumulation that tends to occur naturally in these patients so that it's not causing clinical damage. I'm going to skip forward and just mention that we also looked at brain volume in this study.
We did see, we calculated a composite score that looks at the change in brain volume over 52 weeks and compared that to age-matched controls. We see greater decline in the placebo-treated patients compared to those age-matched controls. We do see a blunting of that atrophy in the active-treated patients. This is a trend that is very intriguing and something that we plan to explore as an exploratory endpoint in phase III. I'm going to skip forward and just say we did have a recent end of phase II meeting with the FDA, where we did reach agreement on all these aspects from primary endpoint populations, dosing regimen, and the key secondary endpoints. That's kind of summarized here in the study design on this slide.
We are aiming to enroll approximately 200 patients who have clinical criteria for MSA, that have evidence of brain atrophy in those MSA-affected areas, and also have elevation of that biomarker, NfL, to distinguish from Parkinson's disease. They'll then be randomized in equal numbers to a treatment with 50 milligrams of ATH434 or placebo, treated twice daily for a year. The key clinical endpoints, again, the MSA rating scale that I showed you before, where we saw such nice efficacy, as well as many of the secondary endpoints that we talked about. In the last remaining minute or so, I'll just tell you that we did do a commercial assessment, where we showed 100 U.S. neurologists a target product profile based on the data that I just reviewed with you.
They had a strong intent to prescribe, with more than 70% being extremely likely or very likely to prescribe based on the target product profile. They clearly recognize the unmet need in this population, as well as the mechanism of action. With relatively conservative commercial assumptions, we estimate peak sales of $2.4 billion. We are well positioned for future catalysts in 2026. As shown here, we've succeeded in our goals in terms of interacting with the FDA. We're now actively preparing for phase III site selection, vendor selection. Finally, we are continuing to prosecute our patent portfolio. We're expecting positive news in the near term on some important IP that will significantly expand the commercial opportunity, both in MSA as well as in Parkinson's disease. With that, I'll close.
Maddy, I don't know if we have time for any questions, but I'll stop there. Thank you.