Okay. Welcome to the Cantor Global Healthcare Conference. I am Samantha Schaeffer on the biotech team with Cantor. With us, we have Alterity Therapeutics, and I am pleased to introduce David Stamler, the CEO. Let us start off with a brief introduction of yourself, followed by a snapshot of the company. Oh, thanks. Yeah. I came to Alterity back in 2017 on the heels of two drug approvals in CNS while I was at Teva Pharmaceuticals. Teva had acquired our San Diego-based company called Auspex Pharmaceuticals back in 2015. I originally came on as the Chief Medical Officer, but a few years ago, I was asked to take over as the CEO as we got closer to the clinic. Company, we are headquartered in Australia, but I was brought on to put a U.S. face on the company, brought a lot of my key team members with me, as you know, drug development is a team sport. Everyone was eager to join and join me on this endeavor to find a new therapy for multiple system atrophy. Perfect. You are developing ATH434 for multiple system atrophy, as you just mentioned. Can you give us an overview of the indication and what does the natural history look like for the disease? Sure. MSA is quite a devastating disease. It is referred to as a Parkinsonian disorder, so it can present and often does present looking like Parkinson's disease. However, the other side of the coin is it is a very aggressive disease. It progresses rapidly, more like ALS. Patients can initially present with nonspecific symptoms, bladder problems, difficulty maintaining their blood pressure when they stand up. But over time, they then progress quite rapidly, develop neurologic symptoms, and then within a few years, require walking assistance. Many require a wheelchair within a few years of symptom onset. The average survival is just seven to eight years. Patients typically receive symptomatic therapies over this period, but they generally do not work well. These patients just lose the ability to ambulate and kind of progress rapidly. It is quite devastating. Mm-hmm. Maybe you could elaborate more on the unmet need of the disease. Yeah. Because they progress rapidly, because they only use symptomatic therapies, anything that can be found to slow the progression is greatly needed. Sometimes you can think of the disease, I mentioned ALS, in some ways you can also think of it like cancer. The disease, anything you can do to slow down the progression is going to offer patients months, perhaps years, of life. Obviously, that's the real goal of therapy. Mm-hmm. Could you walk us through ATH434's mechanism of action and why it's well-suited for MSA? Yeah. ATH434, which I sometimes just call 434, is an iron chaperone. It is known in diseases like MSA and Parkinson's disease that iron accumulates at the area of pathology for a variety of reasons. Once the iron accumulates there, it kind of drives the pathology. What we do with our drug is we bind that iron, and we redistribute it within the cell so that it has a reduced impact on driving the pathology. That is the mechanism, and what is nice is it does not actually try to remove the iron from the body, which can have side effects. Actually targeting the stored form of iron, which is also present in the areas of pathology, can actually have a negative effect. We are a very gentle iron binder, which is why it is referred to as an iron chaperone. It shuttles the iron around the cell. Your bioMUSE natural history work established that iron accumulation is near universal in these patients. How did that data set inform the design of the clinical program? Yeah. Trials in MSA are difficult because identifying patients with early disease, which are the ideal targets for clinical trials, is difficult. As mentioned, these patients can look like Parkinson's disease. They can look like other forms of atypical Parkinsonian disorders, PSP, dementia with Lewy bodies are a couple others. It is really important if you are going to be successful to have a homogeneous patient population. The diagnosis of the disease is a clinical diagnosis, so using clinical criteria alone is fraught with challenges, and that is why using biomarkers is important. That is what the bioMUSE study was all about, bio being biomarker, muse, trying to find the muse of identifying these patients. This is a trial that we did in concert with Vanderbilt University. A neurologist there named Daniel Claassen is an expert researcher in neuroimaging, also sees these patients clinically. We developed a program together where we looked at the neuroimaging, we looked at various biomarkers in spinal fluid and plasma to try and identify those that were most suitable for identifying patients in a clinical trial. That is what we did. We did that test, kind of test drove it in the natural history study, and then we used it in phase II, to identify patients. That is a large reason that we think that we are so successful in phase II. Mm-hmm. That's a perfect segue. Let's move to the clinical data in the ATH434, phase II in early-stage MSA. You reported a 48% slowing of projection on UMSARS part one at 50 mgs. Can you contextualize the magnitude of the effect for us? Yeah. We showed anywhere from about a 2.7- 3.7 difference on that scale. It's been shown independently, in a separate trial in MSA that a difference of 1.5 points between drug and placebo is clinically meaningful, the so-called MCID or minimal clinically important difference. We know that both dose groups exceeded that level significantly. The question is, what is a 2-point difference on that scale mean? The MSA rating scale, or UMSARS, as you referenced, it rates 11 symptoms from 1 point- 4 points. It's quite notable that a 1-point difference on that scale can mean a lot. It can mean the difference between normal swallowing and occasional choking. It can mean the difference between having speech that's understandable versus unintelligible. It can mean the difference between fine motor skills, being able to feed yourself or dress yourself normally versus having significant slowing. On any one of those items, a 1-point difference can be clinically meaningful, so it's pretty easy to understand how a 2 point, 3 point, or 4-point difference is even more meaningful. Anything you can do that can give these patients back time in their day or make them more independent, able to walk without assistance, is another variable that's measured with this instrument, is very meaningful to these patients. Mm-hmm. The primary endpoint of the study, ATH434-201, was change in brain iron content by MRI. What did the imaging data show? Well, the imaging data showed that, to our surprise, and we didn't have a full understanding of the mechanism of action of the drug when we started the study, that we actually demonstrated at the 50 mg dose group trends in reducing brain iron compared to placebo. Whereas in the 75 mg dose group, which was less effective from an efficacy standpoint, we didn't see quite the same reduction in iron. But what we did find was when we looked at how that change in iron correlated with clinical outcomes in a separate analysis, that there was a correlation that if we could actually reduce the iron or, and its relationship to the clinical endpoint in placebo, that we kind of decoupled that relationship in both treatment groups. Mm-hmm. Why do you think the 50 mgs outperformed the 75 mgs? Yeah. We don't always have the answers in clinical development. We know that that dose group is different. We know that they were somewhat milder on the baseline. It's quite possible that their iron deposition, the stage they were at coming into the clinical trial, was more amenable to all the mechanisms by which the drug actually lowers or redistributes brain iron. So we know that there are qualitative differences between the dose groups. We knew that going into the trial, or I shouldn't say going in, but the analysis of the baseline characteristics, that there was something about the 75 mg patients that was more severe at baseline. Beyond the primary clinical measure, the swallowing data really stood out to me. Why is dysphagia the right measure for MSA, and how do you get comfortable making it a key secondary in the phase III? Yeah. Swallowing impairment with many diseases like MSA, Parkinson's, and some of the other forms of atypical Parkinsonism I mentioned, affects the muscles that govern swallowing. That impairment, if you can imagine, whether it's just handling saliva, eating without choking, or just even being able to sleep without kind of choking on your own secretions, can have significant impact on quality of life, and on even morbidity, developing aspiration pneumonia. Swallowing is a really important symptom of this disease. What's important about this scale, this Swallowing Disturbance Questionnaire, is it's a patient-reported outcome. The FDA likes these endpoints because it's a direct report of the patient, and it's a scale that was developed and validated to be used in a variety of diseases, such as Parkinson's disease or MSA. So it's a very useful endpoint. It's easy to administer. It has 15 questions where patients just answer, rate their symptoms from, I think zero to three. It's a reliable scale. We showed a very nice effect on it in phase II. Mm-hmm. Great. At AAN, you introduced a new composite measure, MuSyCA? MuSyCA, yeah. MuSyCA. Yeah. Can you explain what it captures that UMSARS Part I alone does not, and why you chose the 11-item UMSARS Part I as the phase III primary rather than a composite? Yeah. The MuSyCA endpoint is an interesting one. It was developed by a consortium of academics at NYU, Vanderbilt, Medical University of Innsbruck, as well as Mayo Clinic. They are very interested in identifying endpoints that really capture change in the disease over time. So they looked at historical databases and saw that various items of UMSARS I, which are activities of daily living, that is Part I, and then which items on Part II, which is a motor examination, were most sensitive to change over time in this patient population. They identified, I think, about four or five from Part I and a similar number from Part II, and then looked at that. Because that was just published in the last 12 months, we wanted to look at that and apply that new scale to our phase II data. Not surprisingly, we showed a very robust signal using that. What is interesting, and I think belies the difference between how academics think about this disease and how the FDA thinks about it, is the FDA does not like endpoints that focus on motor performance, which is a component of MuSyCA. The FDA is focused on endpoints about how patients feel or how they function or potentially how they survive. So, even though there is academic interest in this endpoint and we wanted to see how our data performed, the FDA is all about how patients function. That is why UMSARS Part I is so important because it looks at these 11 items that assess how patients function from a day-to-day standpoint. Mm-hmm. You also ran the ATH434-202 study in a more advanced population. What does that study add to the package, and how did that inform the phase III design? Yeah. What it showed us was we offered this trial, the bioMUSE study, to patients, many of whom were in the natural history study. We wanted to offer them some potential benefit from receiving treatment. There were other patients that came in that were not in the natural history study. Because our development was focused on the moderate stage patients, those patients who have motor symptoms, but are not so advanced. We wanted to see how patients performed who had more advanced disease. It was a small study. It was open label just in about 10 patients. We looked at many of the same measures that were used in phase II, in the double blind study, both clinical criteria as well as neuroimaging criteria to see how the patients performed. What we saw from an efficacy standpoint was that on objective measures, brain volume was probably the most important one, that the change in brain volume over one year of treatment was quite similar in the more advanced patients, as it was in the earlier stage patients. We also showed that the clinical change on that MSA rating scale, on these global measures of disease severity, was also similar between the two trials. Then probably from the most important standpoint, from a development standpoint, we showed that the safety profile in the advanced patients was comparable to those in phase II. All those are important to help us know that if we do ultimately get approval in the moderate population, that we have some data that shows that more advanced patients tolerate the drug and potentially have benefit. So, it kind of informed our decisions regarding the design of phase III. We still want to target the earlier stage patients, but we know that moderate patients or advanced patients can tolerate the drug and do well. Mm-hmm. So let's turn to the regulatory. In July, you received end of phase II minutes. Can you walk us through the outcomes and what specifically the FDA agreed to? Yeah. We had proposed in detail our phase III design to the FDA that was largely based on the phase II program. We did reach alignment with the FDA on the selection and the scoring of the primary endpoint, the MSA rating scale. We also agreed with them on the target patient population, which was quite similar to the patients that we targeted in phase II, as well as on the key secondary endpoints. We mentioned the Swallowing Disturbance Questionnaire, but also this measure of orthostatic hypotension symptoms, the so-called OHSA, and the Clinical Global Impression of Severity. We also agreed on other statistical methods for how we were going to analyze the data, both how we would stratify the patients based on a certain biomarker, as well as how we would analyze the data, what covariates we would use. All in all, we did align with the FDA on those key aspects of the trial design, which really sets us up nicely for proceeding to the phase III trial conduct. Yeah. Maybe getting more granular into the phase III in more detail, what do you need to see to file? Yeah. One of the questions we asked the FDA was, did they agree to a single pivotal? The answer was essentially yes. Obviously, they cannot agree to the phase II data until they see it. But with the pivotal trial design as we have designed and agreed on that, they agreed that that plus confirmatory evidence from the phase II data would be sufficient to file an NDA. We also did outline the overall size of the clinical trial database with the phase II design as we had presented it to them, and the overall size of the database plus a pivotal trial and the supportive data from the phase II study were adequate in principle. The FDA uses their catchphrase, "It's always a matter of review," until they see the final data, but yeah, that was the outline of what we have proposed and what they thought was reasonable. Mm-hmm. What would the design look like, perhaps, the length of the study? Yeah. The phase III trial is similar to the phase II study in terms of its design. We are going to study the 50 mg dose level, which was the most effective dose, and we did see a plateau of efficacy of that from the phase II. Patients will be randomized in equal numbers to receive 50 mg or a placebo, treated for 12 months, with the endpoints that we have discussed, the MSA rating scales, the primary endpoint, and the key secondaries as I have outlined already. What are the powering assumptions, specifically what placebo progression rate are you assuming over the 12 months, and what treatment effect are you powered to detect? Yeah. We do not typically make an assumption on the placebo rate per se. What we do is focus on what is the drug placebo difference. We are powered, depending on how you analyze the data and how you score the endpoint, anywhere from as low as 2 points to up to 2.5 points, using the standard deviations that we observed in the phase II study. We even have reasonable power to detect as low as a 1.5 treatment difference, which is the minimal clinically important difference. I would say, in general, I feel comfortable that we are powered to detect a treatment difference around 2 points- 2.5 points on the trial, which is, by the way, the less effective of the two dose groups that we used in phase II. We took a more conservative approach. We didn't assume that we're going to see 3.7 points. We took a much more conservative approach, which historically is, I think, the right way to do it. Mm-hmm. And you saw an 8.2 point placebo decline in the phase II. How much confidence do you have that a 200-patient phase III replicates that placebo trajectory? Yeah. It was actually a little bit less than 8.2 point, anywhere from, depending on how you analyze the data, between 7.5 point and 8 points. But we feel confident. We know a lot more going into phase III than we did in phase II. We were somewhat blind going into phase II, that being our first efficacy trial. But we do know that using the criteria for selecting patients, that we are going to select a patient population that we are confident has MSA, and we are using criteria that will help us identify a population that deteriorates similarly to those that we selected for phase II. Mm-hmm. So where does the trial initiation stand, protocol, sites, and drug supply? Yeah. The protocol has essentially been finalized. We've reached that design, so we are in the process of putting the finishing touches on that study design. We've selected our CROs. We've been doing feasibility and site selection for several months now, so we've identified sites. We're identifying patients or clinical sites, and we're targeting probably about eight countries, the United States, Australia, possibly Canada, but also the U.K. and a handful of other European countries, many of which participated in the phase II trial. So that site selection process is ongoing. And then finally, from a drug standpoint, we have successfully manufactured our first registration batch of a drug, and that drug is being tableted and packaged right now. So we will be prepared to release drug to sites in the fourth quarter. We are targeting activating sites by the end of the year, and so we'll certainly have sites active by the end of the year. Maybe screening, we don't know if that's going to happen, whether it's going to be the end of this year or early next year, and then recruitment will commence next year. Mm-hmm. So perhaps by your end, is initiation, when can we expect top line? Yeah. As mentioned, we are going to be carefully selecting patients, so this is not going to recruit quickly. We think we're going to require at least 12 months to recruit, maybe 15-18 months to recruit. But overall, then after recruitment is completed, we assume that the last patient is going to complete the trial. That's another year, and then another three months to clean and lock the database. So overall, we think the trial is going to take about two and a half years to conduct. Perfect. Let's talk about the commercial opportunity. You published an assessment pointing to $2.4 billion in worldwide peak sales. Walk us through how you get there. Yeah. This was independently assessed by a group that is seasoned in doing this. We did qualitative research to start with, where we surveyed about 20 movement disorder neurologists, many KOLs in the area. We developed then a product profile and a discussion guide that was then administered to 100 U.S. neurologists, half specialists, half generalists. They were shown a TPP based on the phase II data that we had generated, and that is part of our corporate presentation. Using, I think, relatively conservative commercial assumptions with a target patient population on the lower side, maybe at peak, just around 20,000. We assumed orphan pricing, which again, is conservative numbers, and estimated based on various assumptions with those that received disease-modifying therapy with payer coverage that, at peak, we only assumed about 5,000 receiving drug. That took us to the $2.4 billion mark at peak. Obviously, with a newly approved therapy, increased awareness, using more generous numbers, in terms of patient numbers, we think $2.4 billion is actually quite a reasonable and achievable number. Mm-hmm. Thinking about the patient population and the penetration, is MSA a concentrated patient population? It is. It mostly will be seen by movement disorder specialists and by high-prescribing general neurologists in underserved areas. We think that a relatively small sales force could really target these clinicians easily. Okay. How many patients are actively managed by a specialized movement disorder? Yeah. We haven't done that careful research, but I would say the majority of patients are seen at specialty centers, at academic centers. There's a group that is doing a lot of patient advocacy in the U.S. called Mission MSA. They have identified centers of excellence, and there are about 30- 35 of those centers identified across the U.S. So that's where we think many of the patients will be seen, but we also know that there are more centers coming online, and it's not just those centers of excellence that will see those patients. Mm-hmm. I see you have a recent patent granted for a composition of matter for ATH434. Does this impact the commercial opportunity? Yeah, so great question. The commercial assessment that we've done that estimates peak sales at $2.4 billion only assumes orphan exclusivity, which would take us out to about 2037 or 2038, depending on when the approval comes. The patent that was granted, which is a composition of matter patent governing the crystalline structure of the drug, will cover the drug out to 2045. In essence, what that does is it doubles the period of exclusivity from 2030 to 2045. Yeah, it has a very meaningful impact on the commercial opportunity for MSA, and in the future, we will probably repeat that assessment and clarify that peak sales estimate. The other thing that the patent does that's really important is it puts Parkinson's disease, makes that a viable commercial opportunity with coverage out to 2045. We can now justify the investment in Parkinson's disease. That's been a real interest of prospective partners that we've been discussing with over the last six months. The patent's quite important, both for MSA and for Parkinson's disease. Mm-hmm. Perfect segue. What is your cash runway, and how do you think about partnering? Yeah. We've recently released in our annual report, which our fiscal year ended in June, that plus recent exercise of some existing stock options that we have, a little north of AUD 30 million in the bank. Partnering discussions have been quite active. There's a lot of interest in this indication. We've talked a little bit about that from a competitive landscape. There are some major players that are involved in that, so there are some large pharma companies that we've been discussing this with, and there is a real interest. We are looking at those partnerships critically. We want a partner that recognizes some of the challenges in development that would welcome us participating in that development activities. We are also pursuing investment strategies. Large biotech specialty funds have been in discussions with us for several months, and we look to pursue that dual track, clarify our financing of phase III over the next month or two. There is a possibility of partnering before the phase III. Yeah, absolutely. Partnering is a distinct possibility. Great. In the last 20 seconds, the last question I have for you is, if we're sitting here 12 months from now, what would you like to say were the key value-creating accomplishments you've had over the past year? Yeah, I think we're certainly aiming to publish the phase II results. That's been an active activity. Obviously, financing the phase III through partnership or through capital raising, or a combination thereof. And embarking on the phase III study, commencing enrollment. With additional capital that comes into the company, obviously, we would also look to bring in new opportunities. We have a very seasoned team of clinical neurologists, neuroscientists, and there are a lot of very interesting assets out there for us to look at and potentially bring in, create additional shareholder value. Perfect. Well, thank you so much, David, and everyone for attending, and looking forward to the progress. Yeah, great. Thank you, Samantha.