ALTERITY THERAPEUTICS LTD (ATH) - ATH434 And The Race To Treat MSA

MSA is rare, relentless, and too often diagnosed only after the most obvious neurological symptoms arrive. We’re joined by David Stamler, Managing Director and CEO of Alterity Therapeutics, to explain what multiple system atrophy can look like from the first vague signs through to rapid loss of mobility, and why symptomatic treatments leave such a large unmet need. 

We talk through the phase two signal for ATH434, including what “48% slowing” on the MSA rating scale could translate to in everyday life, from walking and balance to tasks like dressing and eating, plus the importance of swallowing outcomes and orthostatic hypotension symptoms. David also shares how ATH434 is designed to work as an iron chaperone, why iron biology matters in neurodegenerative disease, and how new endpoints like digital biomarkers can track real-world walking with wearable sensors. 

A major focus is the regulatory path: Alterity’s alignment with the US FDA at the end of phase two meeting, why it de-risks the program, and what the agreed phase three clinical trial design looks like. We cover the practical steps still required before first patient enrolment, the expected timeline to results, what larger partners look for in a program like this, and how manufacturing and patent strategy support longer-term value. 

If you care about biotech, clinical trials, and the hunt for disease-modifying treatments in neurodegeneration, listen now and share this with someone following MSA research. Subscribe, leave a review, and tell us what question you want answered next.

Transcript

Andrew Musgrave

Welcome again to ASX Briefs, and today we're speaking with David Stamler, the Managing Director and CEO of Alterity Therapeutics, a clinical stage biotech developing disease modifying treatments for neurodegenerative diseases. Alterity has just achieved a major regulatory milestone securing alignment with the US FDA on the pivotal phase 3 program for ATH434 in multiple system atrophy. David, thanks for joining me today and welcome to the ASX Briefs podcast.

David Stamler

Great to be here, Andrew.

Andrew Musgrave

David, for listeners less familiar with Alterity Therapeutics, can you provide a brief overview of the company?

David Stamler

Yeah, so we're an Australian listed company, but we have a strong presence in the US as well. I joined the company about eight years, actually nine years ago, to really advance the development in the area of neurodegeneration. The company has a long history of targeting neurodegeneration. And when I joined, I brought a core group of folks that I had worked with in leading a few other drug approvals through the FDA. The idea was that we're going to find a new molecule, find a new indication, and try and address another important unmet need. And that's really what we've done. So, we've been working very hard on this development program to address this orphan disease that has a huge unmet need.

Andrew Musgrave

Now, David, for listeners less familiar with multiple system atrophy, can you please explain what patients are facing, how patients are treated today, and why ATH434's mechanism of action is well suited to address the underlying disease process?

David Stamler

So multiple system atrophy or MSA is, as mentioned, a rare disease. It's a neurodegenerative disease that involves the death of neurons in multiple regions in the brain. It's a rather insidious disease. It can appear or present with not very nonspecific symptoms like bladder problems or sleep disturbance or light-headedness when you move from a sitting to a standing position. That's called orthostatic hypotension. And often times patients will go to various specialists to try and understand what's happening. And it's only when they start developing neurologic symptoms, overt neurologic symptoms like Parkinson's, that's the shuffling movement or the slow movement that many people have seen in friends or family members, or if they start developing an unsteady gait or frequent falls, that's when they come to the attention of a neurologist. Unfortunately, when those neurologic symptoms appear, the disease starts progressing quite rapidly. And patients will typically go from kind of a walking to requiring a walker or a wheelchair within a few years. More than half of patients require a wheelchair within five years of symptom onset. And the average survival is just seven to eight years. So, there's really an urgent need to find a new treatment for these patients. Now, they typically will receive symptomatic therapy for their most important symptoms. So, they can take drugs to treat the abnormal movements of Parkinson's disease or to treat the bladder issues that they experience. And sometimes they work, sometimes they work well, but if they do work well, they only work for a short period of time. And either those pay or in that circumstance or in the circumstance where they don't respond, they really have very little. And the combination of very few therapeutic options along with the rapid progression is quite terrible. And you know, the low blood pressure symptoms that I mentioned and the impaired walking, those take a tremendous toll on people's daily functioning. So, anything we can do to slow down the disease progression really is an important advance for these patients.

Andrew Musgrave

Now the phase 2 data showed 48% slowing of disease progression at the 50-milligram dose. So, how significant is that result clinically, and how does it compare to what's been seen in the MSA trials historically? And what does it mean in terms of real-world outcomes for the patient?

David Stamler

Yeah, so that 48% slowing translates to almost four points of slowing on this scale that we use to measure symptom impairment in you know, functional impairment in many disease areas. That can represent a significant impact. And if you know, it can mean less frequent choking, it can mean faster movements in terms of walking, or even the ability to cut your food or dress yourself or take care of your own personal appearance more rapidly because your movements are more fluid and you're functioning better. So, yeah, 50% slowing has never been seen before in a clinical trial. There have been many attempts at trying to find novel drugs or taking old drugs and repurposing them, but nothing has really demonstrated that degree of slowing that we've shown. So, anything that we can do to speed this along and get it in patients' hands as quickly as possible is really what we're aiming to do.

Andrew Musgrave

In June this year, Alterity announced the successful outcome of its end of phase 2 meeting with the US FDA. Can you walk us through what achieving alignment with the EOP2 meeting actually means in practical terms? What did the FDA agree to, and why is this such an important de-risking milestone for ATH434?

David Stamler

Yeah, so the end of phase 2 meeting as it sounds comes after you've concluded your phase 2 investigations, which we have done with this double-blind study that we've conducted. It's really a critical development event in advancing a molecule through the FDA. And the goal there is to really achieve alignment with the agency on what your next definitive study or studies need to look like. So, you will go in, and you'll propose a very specific study design in terms of the patient population that you want to study, what the endpoints should be, how you want to analyse the data, and what dose you're going to use and how long you're going to treat patients for. So, all that is really the subject matter of that meeting. And the reason it's so important is that you do need to agree on a study design so that if you are successful, that you have reached agreement with the FDA that that study will really support the future approval if it is successful. So that's why it's such a vital milestone in the development of a drug.

Andrew Musgrave

And this EOP2 outcome followed earlier positive type C meetings on clinical pharmacology and manufacturing. Does that broader pattern of FDA engagement give you more confidence heading into phase 3?

David Stamler

Well, it does. And those and those meetings are equally important to the end of phase 2. We structured this series of meetings on late last year and have been kind of talking to the market about it over this period of time that we did want to have these series of meetings. So, the first one was this so-called type C meeting to focus on the animal work, the additional animal work that we needed to do and needed to complete before we could start the, you know the definitive phase 3 trial. So, that was an important meeting to have and to reach agreement with the FDA on. The next one is, was the chemistry and the manufacturing. So this is where you basically talk to the FDA about how you're going to make your drug, what you're going to, how you're going to start the process of synthesizing the drug, how you're going to control for various aspects of the manufacturing process and kind of how you're going to set the specifications for saying, hey, we've done this in a controlled way and we're successful. So, those were equally important legs of a stool, if you will. And the end of phase 2 meeting was really the third important meeting to reach agreement with the agency. And you really do need agreement on all three fronts in order to proceed satisfactorily.

Andrew Musgrave

Also, since the phase 2 data was announced, you've presented at a number of medical conferences and have published some new data. What have you learned from some of the new findings and what sort of feedback have you been getting from clinicians at those presentations?

David Stamler

Yeah, so we've presented new data on various endpoints that are really important in this patient population. One notable one that I made reference to is swallowing. So, I presented at a conference in London back in May where I disclosed that we had a very meaningful effect on reducing swallowing impairment in the patients who received ATH434 compared to those who received placebo. We've also disclosed important data that really underscores the mechanism of how the drug works. We actually showed that, you know, we target iron with our drug. We actually act as an iron chaperone where we kind of redistribute excess iron that is driving the pathology in the brains of these patients. And we showed that by treating patients with ATH434, that we could kind of reduce the pathology, the downstream pathology associated with that iron accumulation and that was present, we presented it at a webinar back in late April, and that webinar is available at our site for anyone who's interested in learning more. I think it's a really fascinating story. It underscores how the drug works. It also underscores this wonderful collaboration that we've had with Vanderbilt University and the lead investigator who's really overseeing all the neuroimaging. That's Dr. Daniel Clausen. He recently joined as our chief medical advisor. And I think this program has really been a collaborative effort between his research lab, and our organization, so what this has shown is that you know we we've been collaborating successfully for several years and have shown that we've really made excellent progress in understanding how the drug works and how that mechanism really translates into a patient benefit.

Andrew Musgrave

Looking now at the phase 3 trial, can you describe the planned phase 3 trial design? How many patients, what's the treatment regimen, and what are you measuring at the primary endpoint?

David Stamler

Yeah, so as we agreed with the FDA, the phase 3 study is going to be approximately 200 patients. Patients will be randomly assigned in equal number to either ATH434, the 50-milligram dose, or a matching placebo, and they will be treated for 12 months, as we did in phase 2. The primary endpoint in the study, which is really how you measure the success of the trial, will be the MSA rating scale. And that's the scale you referred to previously, where we saw the 48% slowing in the phase 2 trial. So that is the most important endpoint and the primary endpoint for the study. But the important secondary endpoints are the swallowing disturbance, as mentioned using this a questionnaire that the patient fills out. There's also a secondary endpoint that we use to assess the symptoms of low blood pressure when people go from a sitting to a standing position and then we will look at various other secondary endpoints that will assess various aspects of the disease.

Andrew Musgrave

With trial activities targeted to initiate by year end 2026, what are the key milestones between now and first patient enrolment?

David Stamler

Yeah, so right now our team is working very hard in setting up the study. We obviously have to finalize the protocol. So, we're taking the advice that we learn from the FDA and working on that protocol. We have to complete the drug manufacturing process, which has been something we've been working on seriously for you know well over a year with getting it ready for the definitive studies and for ultimately commercialization. That has gone according to plan, but you have to work hard and characterize the drug, successfully manufacture, and then make it into tablets. So, that's another critical step. And then finally, you know, in setting up the study, we're going to select vendors that are going to help us manage the study and then select sites. You know, we're targeting upwards of 40 to 50 sites who are going to help us recruit patients into the study and then once we do that, we'll seek regulatory the final regulatory stamp of approval. And then we'll, you know, be able to activate sites by the end of this year. That's our goal.

Andrew Musgrave

And if you look at the timeless for the phase 3 trial, when do you think you may expect a readout or potential approval?

David Stamler

Yeah, so we expect that, as mentioned, we'll start activating sites by the end of the year. We believe that the recruitment is going to take us about a year to a year and a quarter to recruit. And then if the last patient who enrols finishes, that's an additional year and then a few additional months to clean the data in the database and then lock the data and then unblind the results. So, we expect if things go according to plan, we will have a top line result in the middle of 2029. and then it's based on those data that we would then go to the agency and then seek to apply for you know a new drug application to approve and register the drug.

Andrew Musgrave

Looking at partnerships now, your disclosures suggest potential licensing or partner interest from larger biopharma players. Without getting into specifics, what is the typical profile of a potential partner?

David Stamler

Yeah, so we've had a tremendous amount of interest from prospective partners, anywhere from big pharma companies that people who know the industry would recognize, and some mid-sized companies as well as some regional players. The ideal partner is someone who appreciates the complexity of working in this development area. We think we have a unique approach in terms of selecting patients and identifying them. And I think a prospective partner would you know certainly welcome our input on the development, but that partner would also have their own drug development experience, success, previous success in commercializing drugs within the United States and Europe and there are many such partners that we've been talking to.

Andrew Musgrave

And which aspects of the ATH434 data set and planned program resonate the most in your conversations?

David Stamler

Well, I think it's largely what we've talked about. I think the efficacy signal on the MSA rating scale is first and foremost the most important endpoint to demonstrate efficacy on. But you know stabilization of swallowing in these patients, the stabilization of symptoms of the light-headedness associated with low blood pressure, those are also important. And the other data that has resonated very strongly, not only with partners, but with clinicians in the field, we haven't talked about this, are so-called digital biomarkers. This is where you can actually assess patients' ability to walk in the outpatient setting. So, patients would typically wear a sensor at the baseline of the trial, and then every few months thereafter, and we can look at how many steps per day they would take or how many minutes of walking. And we've shown that with our treatment that we can actually significantly improve the ability to preserve walking with treatment. So, all those data are really important. Not the and I forgot to mention the safety, and the safety profile has been excellent. So, the combination of both is really critical for establishing a new a new treatment.

Andrew Musgrave

Now, just touching on the financials, can you run through what the phase 3 funding strategy could look like?

David Stamler

Yeah, so we've got a pretty strong balance sheet right now, which is going to help us successfully do all the preparation we need to go into phase 3. I think our main focus is really trying to find that ideal partner who can help us finance the trial, you know, minimize any potential dilution from additional cap raising. And that will be our goal as we go forward. We you know, I think the strong interest that we've seen to date in conjunction with the strong data that we've had, you know, puts us in a good position and makes us feel confident we can really do this, do this successfully with the right partner.

Andrew Musgrave

Finally, David, as you look to the second half of 2026 and into 2027, while we wait for the phase 3 activities to start, what other catalysts and progress might we expect?

David Stamler

Yeah, so you know, we're we've been working on the publication of the trial. So, we expect in the near term that we will be able to, or we hope to report, you know, some progress in in advancing the publication. The other thing that is worth noting is that we have been very actively pursuing a patent strategy for ATH434 and we have filed a couple of patents about a year ago, one that covers the dosing of the drug and the use of the drug in the treatment of MSA. When that patent has been published, and we're quite confident that that is going to extend the commercial life of the drug beyond what we've already shown. The other patent that we're that we're looking at and waiting on is one that's really designed to cover composition of matter of the crystal structure of the drug. Those are quite robust patents. Those are really important for protecting the molecule, not only for the use in MSA, but could also open up the opportunity for us to actively pursue development in Parkinson's disease. So, we've got a keen interest in looking at other indications like Parkinson's disease, other indications where iron plays an important role in disease pathogenesis and those are things that will really be enabled by new patent protection on the molecule. So, I would say I would encourage investors to kind of keep an eye out for things like that.

Andrew Musgrave

Okay, David. Well, it's a genuinely exciting time for the company and for the MSA patient community. So, it's been great to chat today. Thanks for your time, and we look forward to further updates in the upcoming months.

David Stamler

Great. Thanks for having me.

Andrew Musgrave

That concludes this episode of ASX Briefs. Don't forget to subscribe, and we look forward to catching you on our next episode.