Syntara Limited (SNT) Earnings Call Transcript

Thanks for standing by and welcome to the Syntara Investor Webinar and Q&A for this morning's announcement of the preliminary analysis of the Phase II trial of SNT-4728. [Operator Instructions] On the webinar from Syntara, we have the CEO, Gary Phillips; and the Chief Medical Officer, Jana Baskar. And joining them are Simon Lewis, who's a neurologist and the trial's principal investigator. He's also the Director of Parkinson's Disease Research Clinic at Macquarie University. To begin, I'll hand it over to Gary. Please go ahead.

Thanks very much, Matt, and welcome, everybody, and thank you for bearing us some time today. Matt just introduced the 3 people on there. So we've asked Simon to come along and join us because we understand that this study is -- it was a technically challenging study, and being the first study of its type studying a medication like iRBD. There's a lot to unpack and think about as we move forward. And I think just at the outset, I'd also say this for Syntara shareholders, this was a study that was fully funded by Parkinson's U.K. We're very grateful to them for their support in getting us to this point. And Professor Lewis, Professor Ho from the U.K. were instrumental really in pursuing and building the design of this study. and in front of Parkinson's U.K. and other philanthropic bodies and getting the funding for this. So this is a great outcome that we've had today as the first set of information coming out of this study. So if we just go back one step and briefly looking at iRBD in Parkinson's. So patients with this sleep disorder, isolated REM sleep Behavior Disorder, they do act out their dreams. So -- and it's not just a bad dream. They become very variable. They shout. They've also been very physical as well. and their partners describe the problems of living with a patient with iRBD as much as the iRBD patient themselves. But the thing we know about iRBD now is that it represents a prodromal stage of Parkinson's and many of these patients go on. In fact, a vast majority of them go on to develop Parkinson's or Lewy body dementia or multiple system atrophy in later years. So it's an ideal opportunity to try and look at this group of patients who go on to have these devastating diseases and to see whether an intervention earlier on can actually have an impact on them and to slow or if we stop the progression to those diseases. So it's a disease where there is there is at least the approved treatments, but standard of care is actually melatonin. So not really any effective treatments. No approved therapies and this study was the first interventional study with a drug which treats the inflammation, which we think is associated with the disease. So with that, I'll hand over to Jana to talk to you about the design of the study and what we set out to do.

Thank you, Gary. So what you can see there in front of you on the right is the study design of this Phase II study run with sites here in Sydney as well as in the U.K. a placebo-controlled study, assessing the effect of SNT-4728 on brain inflammation in patients with iRBD. So we plan to randomize 40 patients 3:1 active to placebo and treating them for 12 weeks with the 15-milligram dose of SNT-4728 for once-daily. Now it's important to point out that this randomization of 3 to 1 was really done to maintain the blind for both the patients, the investigators as well as the people that analyze the results. So it's not really a comparison versus placebo. We'll be able to get into more detail on the next slide, that is really there to maintain the blind. Now the key inclusion criteria in this study was requiring definitive iRBD diagnosis as well as having mild symptoms of parkinsonism and either having both a reduced melt or hyposmia or reduced color discrimination. Now one of the key parts of the study was the PET analysis, which you'll see later, but the PET scans were done both at baseline about week 12. And as you can see, there's a washout period as well after treatment for 12 weeks, which is very important because this study remains at this point, blinded in terms of we're still waiting a database lock. We can move to the next slide. So in terms of the endpoints that are being analyzed in the study, if we look on the left with the primary end point, 2 points to point out first. With regards to the PET, the changes that we were looking for were looking at TSPO. So the translocated protein ligand binding on PET imaging in the stride cortical regions of interest in the brain comparing baseline to week trial in the active arm. Specifically, this was in the substantial IGRA the caudate nucleus, the putamen as well as parts of the oxipetal ortex. We were also looking at safe as well with respect to adverse events, treatment-emergent adverse events and SAEs and also looking at compliance as well. Now in terms of secondary endpoints, with regards to the ligand binding, the idea was to look at all the other regions of the brain that weren't being assessed in the primary analysis. So these are other subcortical and political regions of interest. But again, looking at the active arm from baseline to week trial, so essentially using those patients as the one control from baseline. And interestingly, data that we can look forward to later in this quarter are the exploratory end points here, which were changes in clinical measures relevant for this condition, iRBD, from baseline to week 12 and from week 12 to week 24. And also we'll be looking at a digital and liquid biomarkers as well that are relevant to iRBD or brain inflammation. We can move to the next slide. So with respect to the study itself, we ended up recruiting 41 patients in total with a median age of 68 years, and 93% of them were male. 90% of these participants had reduced or loss of sensor smell, 46% of them had low color discrimination. And interestingly, 95% of these patients had misfolded alpha-synuclein detected in the surprise fluid. So in essence, Prof Lewis and Prof Hughes and their study teams recruited an enriched IRBD population that are at a high risk for phenocommission to Parkinson's and related diseases. Now with respect to exposure and safety, this is really in keeping with the excellent safety profile observed in the prior Phase II studies, where I believe, around 150 participants were treated with SNT-4728 in the previous Boehringer studies. Again, we saw safe and tolerated profile. Specifically, because as I mentioned, based on safety data is not unblinded as the study is ongoing. So what you're seeing there on the 3 bullet points in the second part of the slide is essentially aggregated data because we haven't broken the blind. So across the treatment arms, there were 125 treatment emergent adverse events in 27 patients, all grade 1 or 2, none of them were series. So this is not untypical of a trial like this where adverse events, whatever they may be are reported in a clinical trial setting. So out of the 125 TEAEs, only 14 were considered related in 5 patients. And of note, the most common TEAEs were headache, approximately 19.5% and nasopharyngitis, which is a common cold or constipation and dizziness as you can see. So because this study is ongoing, the blind hasn't been broken as yet, but the safety profile is incredibly encouraging and as expected from the previous study of this compound. So with this, Simon, I'll just be keen for your comments, I guess, firstly, on the male preponderance, is that something that is unexpected here and as well as just your general thoughts on the safety profile observed in the study today.

So I think the sense profile is easy because I think it looks like a very safe drug, which is one of the reasons we're keen to progress with it. And we had obviously the data from the other trials that will hand but really, we're not seeing any signal here that raises any alarm bells grant to a small sample size, but all were saying never want to see anything serious. And then in terms of the demographics, we know that diseases like Parkinson's and Blue body dementia do have a mail preponderance. And as such, it's not a surprise that more men have isolated remet behaviors orders as part of the prodrome of those diseases. And then typically, when people are being asked to participate in clinical trials, you'll see a mail bias main, I think, more willing to engage clinical trials. So I think those things are all very consistent with what we would have anticipated before half.

All right. Thank you, Simon. Now one of the most exciting parts of the study that we're seeing so far. It's been a number of years for me personally to wait for this outcome. And yes, we were really quite excited to see the reduction in inflammation. So if you look at the right-hand part of the slide, there was a statistically significant reduction in brain inflammation observed unilaterally in the putamen part of the brain. There was a mean change of 0.0 -- reduction rather of 0.016 with a statistically significant p-value of 0.0145. Now encouragingly, 20 out of the 30 patients on active treatment, which you can see on the left-hand graph there, that were treated with SNT-4728 recorded a reduction in inflammation from baseline. And encouragingly on the right, even when compared to placebo, there was a significant reduction in inflammation as well to supporting those findings. Now there was no statistically significant change in inflammation detected in other predefined regions of interest in the primary analysis. There were some findings noted in the temporal lobe. But going back to the comparison with placebo, there was no significant reduction in brain inflammation in any region for the placebo group. So encouraging from our perspective. But I'll be keen to hear from your viewpoint, Simon, I guess the importance of this finding in the putamen with relevance to this condition and also this unilateral finding did you find that surprising.

So I guess a quick neuroanatomy primer. So in diseases like Parkinson's dementia new bodies -- what we know is that the neurons that make a chemical called dopamine and neurotransmitter are the ones that take the biggest hit. Now those neurons start their journey down in a part of the brain called the substantial lira but they project from the up to deeper parts of the brain, the putamen being one of those areas that's most implicated in movement. So when we see patients with Parkinson's disease and dementia erode, when we talk about Parkinson's is, we're talking about physical changes, so slowness of movement, typically and other features like tram stiffens. So in actual fact, the putamen is the area that normally takes the biggest hit in terms of losing those opener projections and diseases like Parkinson's and lewy body dementia are unilateral when they start. As the disease progresses, that can become bilateral, but usually remains asymmetric with onside being done. So here, we see, if you like, an area of the brain that is involved in the physical symptoms associated with Parkinson's and lewy body dementia to make sure being the area of picked up. And the fact that it's unilateral, I guess, may reflect the underlying pathophysiology, especially at this very early stage where these patients may not go on and get diagnosed Parkinson's or lewy body dementia 4, 5, 10 years from now. So I think this is a very interesting finding and certainly aligns with some of our thoughts about the disease itself.

Thanks, Simon. If we move to the next slide. So what are the next steps going forward? So as I mentioned, the digital biomarkers is something to look forward to where cognitive function is being measured. There's a smartphone motor assessment as well assessing motor function and actigraphy of these patients had to wear this double or this band around their risk to capture their movements during the study. So all that data will be aggregated and analyzed towards the end of the quarter. Now biological nukes are quite interesting. There's a whole suite of its being measured here looking at inflammation and neurodegeneration both in the blood and the cerebrospinal fluid as well. that will also come through later this quarter. And all that sort of ties up to the analysis that we'll be doing, leveraging artificial intelligence to look at the PET data and compare looking at the liquid and digital biomarkers and seeing whether there's some sort of correlation there occurring. And likewise, we'll be doing that with the clinical data as well and looking at the correlation with the digital biomarkers such as the smartphone motor assessment as an example. And we'll be looking at the drug in des changes analyzing that with respect to patient status and comparing it to baseline, which will help inform the subsequent study down the track. So with that, Simon, just keen to hear your thoughts sort of in a -- from a summary perspective and what you're sort of looking forward to in the coming months?

I think just to touch on the point you raised about some of the results we haven't yet seen the digital biomarkers. So many people will recognize that this is a study targeting participants who don't yet have a diagnosis of a disease. And what I mean by that is when somebody comes at the moment to see a neurologist for diagnosis, they'll typically have very obvious physical features. So slowness of the hand, somebody moving very, very slowly. And that's a very rough way of looking at something that could be much more subtle via 10 years ahead of that time. And so the digital biomarkers, which may be able to pick that up, which may not be obvious to the naked eye, I think are going to be helpful and may align with what we're seeing with this change in that area of the branded curtailment that controls physical movement. The other biomarkers, the biologicals, I guess, we're focusing here on the inflammation and the spinal fluid was taken from every participant at baseline. And in that spinal fluid, we're going to be able to measure markers of inflammation. Now it may well be that see markets will help us to understand which participants had a better response or a lesser response. And similarly, in the blood, there are a number of biomarkers that we can look at the levels of inflammation and see if they've changed between baseline and treatment and also some markers of cell death. And so people are getting more interested in seeing changes in those biomarkers that might be associated with cell death. But I guess to wrap it all up, what we've done here is taken a group of people who don't have a disease, but we know that they're at risk. The fact that the spinal fluid test demonstrated that the vast majority of these participants tested positive for the alpha-synuclein protein, which is what we would associate with getting Parkinson's disease or dementia, lewy bodies, and tells us that we really do have the right cohort here. We just don't know when they're going to progress. And in actual fact, as I mentioned, the fact that this can happen in years, here we are in a study where we've exposed participants to just 3 months of treatment, and we've seen a positive signal. So I guess that no of us want to get too excited right now. But it would be very easy to be sitting here today. So there's nothing -- there's no signal there what can we make in this study. But actually, I think there is quite a lot to make of this study and hopefully more to come.

Thanks, Simon. So just to wrap it up before we go into the Q&A. I was sitting here with a smile on my face today. I think this was a free shot for our shareholders with a drug that was being repurposed from inflammation in fatty liver disease when we sold it to Boehringer. It's come back. This is a drug that still has a patent with extensions that goes out to 2038. And on the back of these results that we've seen today, we filed further patent to extend that even further. So this is a drug with a lot of life left in it and with a real opportunity now that we've seen this initial results from this study. And I think I'd just remind those this is real first interventional study to directly target neuro inflammation in these patients. As such, it was quite exploratory in nature. The regions of the brain that we looked at, we know as Professor Lewis has said, are involved in Parkinson's. But we don't really know what role they play in earlier disease in iRBD and which ones of them trigger as we go from iRBD into Parkinson. And this study was only 3 months in length in patients who have a long journey of LBD to Parkinson's, which can take more than 10 years for some patients, although would appear in the group of patients we selected those, which we think might migrate a bit quicker. And despite all of that, we've shown that statistical reduction in an area which is implicated strongly in Parkinson's. So really pleased with the start that we've made real credit, I think, to the investigators and the patients and the centers which took part in this study. It was a logistically challenging study given the need to give a radio labeled ligand inflation in a PET scan when the half-life of that radio labeled ligand was really, really short. So all credit to the investigators and the patients for getting to this point where we've got data coming in. And very excited to see what happens next. And Matt, I'm happy to hand it back to you now and take any questions that the audience has.

Thanks, Gary, to Simon and Jana as well. [Operator Instructions] The first one I have is congratulations and thanks. Could you please elaborate on the unilateral change in putamen. Is it a benefit -- is a benefit only in the right side versus left side a surprise?

I think we touched a bit on that in the questions, but Simon, perhaps you could reinforce that.

Yes. So I think -- I mean, I guess, having done a number of trials the first surprise is you're getting a signal that it's pleasant of products. I think that the bigger question that goes through my mind is well, would we see a unilateral improvement if this exposure have been, let's say, 6 months. Now the way that this trial was constructed, it was really to look, okay, as an exploratory study do we see any signal that might give us confidence moving forward. As I touched on the disease in terms of its pathology does start in one side of the brain rather than the other. The fact that it was one side versus the other here may reflect that, that was the distribution that we saw in the participants in this study, and we're seeing a stronger result because of it. But having said that, it really, I think, is going to be more questioners a signal that gives confidence that actually if this drug was in the system for longer, given that this process of cell death is quite slow, whether we would see a more generalized response. And I guess that's the most exciting part.

Next question is, based on what you've seen thus far, what do you need to see or what would change your mind regarding taking the drug forward? .

Well, I think from a company perspective, we've seen enough to know that the drug is going to be interesting in this area of these patients. I think it's reinforced the -- we knew this drug was would have with an anti-inflammatory effect, right? We've already seen its anti-inflammatory effect in the systemic circulation when used in patients with other diseases. So we were expecting to see something, and I think that it crosses the blood-brain barrier and this is an early sign after only 3 months, but a really positive one. So in terms of what happens next, we will be looking to see the results that come in the next quarter to see if they reinforce what we're finding or not only reinforce, but further explain the results that we're seeing. During this time, we'll be talking and engaging with our collaborators with the Parkinson's community with Parker's UK, Microtech Fox Foundation in terms of their research priorities going forward. And really, this drug is an opportunity because as Simon mentioned, actually, and I think it bears repeating is that these patients come into the study and they don't actually have a disease. I mean they have obviously iRBD and the symptoms of that. But otherwise, they don't yet have Parkinson's. So if you're going to give these patients a drug, it needs to be safe. And we are very fortunate that we have a drug that is very well characterized. It's been very well developed. In fact, I would say that this drug is ready to go into large-scale Phase III studies given the amount of work that's been done on it. We know the safety profile is really good. It's an ideal candidate from a safety perspective to go into longer-term studies in patients with this disease. And thankfully now, we've now got an early sign of efficacy, which I think we will continue to explore with the rest of the day to come in and discuss with our clinical experts and with the Parkinson's community more generally.

Thank you. Next question is thinking long term, would 4728 be eventually targeted at prediagnosis patients at risk of Parkinson's? And is this cohort currently a routinely screened and identified cohort? In other words, how would you find your patient group?

Well, I might just tackle the indication in my go for, and then pivot it to Simon to talk about whether he sees these kinds of patients coming into his clinic. I mean I think there are 2 potential opportunities. We will, I guess, see further light on as we get the rest of the results in the next quarter. Clearly, there is a belief that if we can reduce inflammation in areas of the brain, which do go on to trigger Parkinson's, that there's a role here for the drug longer term to slow or stop the progression to Parkinson's, lewy body dementia. So that's one thing. The other one is that these patients with iRBD don't really have any treatments at the moment. And there's something like 8% of patients over the age of 70 -- of the population over the age of 70 have iRBD in some form. So there is actually a clinical unmet need for these patients. And when I talk a lot at conferences and I talk to investors and often approached afterwards by people that come up and chat to me about the drugs that we've got in our pipeline and come up with stories of their friends, their relatives people, they know that have had Parkinson's and they had sleep disorders before they were diagnosed and didn't realize it was connected. Simon, perhaps you could talk a bit about your experience of these patients and diagnosing them. Do you think we're diagnose more if we had a treatment?

So I guess the other thing just to throw into the mix, especially for an audience like this, is that the reason we did this study was because there's research out there that identified neuro-inflammation in patients with isolated premier disorder and that in actual the imaging information correlated with the amount of dopamine cells that were dying over the subsequent 3 years. People have considered, of course, the well of new information in Parkinson's disease and dementia with Lewy bodies. So it is not inconceivable that, that process of new information is something that's driving those diseases, too. Now the reason we didn't I guess, push forward and say, let's do a trial in Parkinson's disease because I think that is a much more diverse group. But it begs the question whether that population at the time of diagnosis, may still have new information that's driving their disease amongst other processes perhaps. So that's another population that needs to be considered. In terms of the iRBD population, the truth is that at the moment, there are probably over 50 centers internationally who are part of the international iRBD study group who are waiting on these results. And they are all characterizing these participants in a standardized table fashion. On top of that, the Michael J. Fox Foundation have also started assembling a cohort of participants who are at risk of getting Parkinson's either because of their reporting dream behavior or they're losing tens of now. So I think the bottom line is there is an increasing awareness. And of course, part of the problem is, well, doc, if there's nothing you can give me, why would I need to know? And I wrote an article for the Medical Journal of Australia maybe 10 years ago now, try to raise awareness of this condition amongst GPs because in terms of identifying the cohort, this is a relatively easy population to find in many ways because what we're not talking about here, we're not about sleep walking, not to let children that wondering there's -- what we're talking about is somebody probably over the age of 50, who for no reason, has started acting out their dreams, hunching kicking screen. And that's a very big change. It's not like saying, well, I feel a bit stick in the morning, I feel my smile isn't good. If you're starting to fall out of bed, this is a very clear thing. So I think if there was a pathway and an awareness that actually you could do something and you're at risk of getting these diseases my catch phrases don't sleep on dementia because in actual fact, if we could choose who we're going to target, if the people who haven't got a diagnosis because you've got more cells to same but it doesn't mean to say it couldn't be useful in those other diseases.

Okay. The next question is, would the safety profile support use in this population?

Jana, do you want to...

Yes. yes, sure. So bearing in mind that this compound has been studied in diabetic retinopathy mesh before. with the 10-milligram dose and now with the 15-milligram dose being studied here in this iRBD population, it would definitely support longer-term use in a clinical trial. I think that would be the best answer for this, and we'll have to study it in the next stage. But there's nothing stopping us from doing that are very comfortable to do so.