Neuren Pharmaceuticals Limited (NEU) Earnings Call Transcript & Summary

Good morning, all. Welcome to Neuren's investor webinar on the Phase II results for Pitt Hopkins syndrome. My name is Gerry Zhao, VP of Corporate Development at Neuren. Joining me on the call today from Neuren are Jon Pilcher, CEO; and Liza Squires, Chief Medical Officer. Jon and Liza will make the presentation today, then all of us will be available for Q&A session following the presentation. [Operator Instructions]. Before we start, I would like to remind everyone that we will be making forward-looking statements during today's call, which are subject to risks and uncertainties that may lead to different outcomes. I'll now turn the call over to Jon to start the presentation.

Thanks a lot, Gerry. Good morning, everyone. Thanks very much for joining us. Also thanks to Monsoon and FB Rice for helping us with today's webinar. So look, we're really excited to be sharing with you today the top line results from our Phase II trial of NNZ-2591 in Pitt Hopkins syndrome. And the way today will work is I'm going to give some introduction and then I'll ask Liza to go through the details of the trial results. And then I'll come back at the end and talk about NNZ-2591 more broadly, and then we'll take Q&A. So there's a lot to get through, so we'll move at a pretty rapid pace and hopefully not keep you for too long. So I just want to start by just talking a little bit about Pitt Hopkins syndrome and about the families and patients that have participated in this trial. You have heard me say before that for these Phase II trials that we've run, the protocol is extremely onerous and challenging and the reason is because it's the first time the drug was trialed in patients, and it's in kids, vulnerable populations. So we have to be extremely and appropriately cautious from a safety point of view. So a huge amount of safety monitoring in these trials. And it's not just regular visits to the clinic, which might involve significant travel, it's visits to the home from home nurses. It's multiple blood draws, multiple medical procedures. Really challenging. And to be honest, if you weren't dealing with Pitt Hopkins syndrome, it would be challenging to get through all of that. But of course, these families are not only looking after their child with Pitt Hopkins syndrome and all the problems that come with that, but they've got their normal lives and other siblings to look after, too. So I seriously take my head off to these families for seeing this trial through. And I'm so happy that it's been worth it when you see the results that we've seen. And if I think back to our journey in Rett Syndrome, those families who took part in the very first trial we ran in Rett Syndrome, all that time ago. They're the heroes of the story in some way, they put their faith in us when no one has seen anything about the drug before. So I can't thank those families enough. I also -- the challenges of the protocol also mean it's difficult for the site staff and the investigators. So again, huge thanks to them for getting this trial completed successfully. I also want to thank the Pitt Hopkins Research Foundation, who've played an important role in this as well, and we'll continue to do so as we move forward. And all of those parties have been involved in the development of these Pitt Hopkins-specific endpoints of the -- efficacy measurements that we designed specifically for Pitt Hopkins, and it's clear to us from the result on this trial that you need these specific endpoints that we've included a lot of other endpoints that are not designed for Pitt Hopkins, they're designed for higher functioning populations and different populations and they're not appropriate to use in this population. So it's clear to us that we need to use this these endpoints that have been specifically designed for the population, and they've worked very well in this study. The last thing I want to -- or people I want to thank is the Neuren team. So no one has ever done a trial like this before in this population. And so again, it's taken a lot of skill and a lot of determination to see it through and get to this result. So a huge thanks to them as well. So before we get to the trial, just a reminder of why we felt confident going into doing this trial, and that was the mouse model, the mouse model of Pitt Hopkins syndrome, where you disrupt the TCF4 gene, which is what causes the syndrome. And what we saw in that mouse model was that in every measure treatment with an NNZ-2591 basically changed the impaired mice back to be indistinguishable from the wild-type mice. We didn't do quite as much as we've done in Phelan-McDermid syndrome. You might remember in there, we did a dose-ranging study, and we also did some biochemical and physical analysis. We didn't do that in Pitt Hopkins syndrome, but this result looked very similar to the equivalent in Phelan-McDermid syndrome, which made us feel good going into the trial. So the highlights of the result. Firstly, obviously, given what I just said, safety is really important here, and we're very pleased with the profile that's come out of this. It's very similar to the Phelan-McDermid trial. Saw nothing in lab values and safety parameters and the adverse events. There were no serious adverse events. Nearly all of them are mild. So yes, we're very pleased with the safety profile, which puts us in a good position from a risk-benefit balance point of view. Excitingly, we got statistically significant improvement from baseline and it was assisted by both the clinicians and the caregivers across all 4 of the efficacy measures that I mentioned that have been specifically designed for Pitt Hopkins syndrome. So p-value is a long way less than 0.05. Remember, this is not against placebo, it's an open-label trial. So this is effectively saying what are the chances of these changes from baseline being by chance alone. So very pleased with that outcome. And then more specifically, really pleased with what we saw in the 2 global measures, the one that's physician measure, the CGI and the one that's the caregiver measure, the CIC. So CGI mean score of 2.6. You remember in the Phelan-McDermid trial, it's 2.4 and 9 out of 11 children showed improvement. And on the caregiver measure, a mean score of 3 with 8 out of 11 showing improvement, the equivalent in the Phelan-McDermid trial's 2.7. So really happy with that outcome. And importantly, improvements that we saw, again, this is like the Phelan-McDermid trial, they were in things that are clinically important in Pitt Hopkins syndrome. So communications, social interaction, cognition and motor abilities are the things that sort of shine through when you look at the domains of these measurements. So that's the result in a nutshell. I'm going to ask Liza now to take you through some of the detail of the trial. Again, we're going to move quite quickly. So start off with the design of the trial, please, Liza. Over to you.

Thank you, Jon. Good morning, everyone. This Phase II trial was conducted in children and adolescents at 5 sites in the United States, with special expertise in Pitt Hopkins syndrome. These sites were Rush University, University of Texas Southwestern, University of California San Francisco, University of Alabama, and Colorado Children's Hospital. 16 participants were enrolled between the ages of 3 and 17. The primary endpoint for the study was safety, tolerability and PK. Secondary endpoints included 14 efficacy measures, including 4 specifically designed for PTHS at the -- noted here in the middle of this slide, the CGI-I, the caregiver impression of change, clinical improvement global -- clinician global impression of severity and the symptom-specific caregiver top 3 concerns. As Jon mentioned, there were 10 other non-PTHS-specific measures that have been previously used in other conditions. The study design was that participants entered a 4-week screening and baseline period before a 6-week dose titration from 4 milligrams to 8 milligrams and ultimately to the target dose of 12 milligrams per kilogram twice a day. They were then in the trial for an additional 7 weeks with dose stabilization and following week 17 had a 2-week safety follow-up off-study drug. A key objective of this study was to select primary efficacy endpoints, endpoints for a registration study. Next slide, please. 16 participants enrolled in the study and 11 completed. One subject was discontinued due to being unable to complete safety -- protocol specified safety monitoring. 4 subjects discontinued due to treatment-emergent adverse events. These discontinuations due to TEAEs that were all mild and moderate and all resolved. 2 were unrelated to study drug, 1 participant with COVID-19 and another with mild vomiting, diarrhea and lethargy. 2 related to study drug, including 1 participant with moderate constipation, self injury and abdominal distension as well as fatigue. 1 participant discontinued due to mild sleep disorder and constipation. Next slide, please. The mean age in the study was 9.1 years, and the median was 9.5. There were 11 children between the ages of 3 and 12 enrolled and 5 adolescents between 13 and 17 years. There were 8 females and 8 males. The cognitive level was notable for 15 participants having a nonverbal IQ or developmental quotient of less than 35 and one participant having an IQ over 35. The completers in the study had an average or mean developmental quotient of 12, which is in the profound range. Clinical global impression of severity at baseline for the population had a mean of 5.0, which is markedly impaired. Next slide, please. NNZ-2591 was well tolerated. All treatment-emergent adverse events were mild to moderate and mostly not related to study drug. There were no serious treatment-emergent adverse events. And as previously mentioned, there were 4 discontinuations due to TEAEs, all mild to moderate and all resolved. There were no meaningful trends in laboratory values, ECGs or other safety parameters observed during treatment. On the right-hand side is the table of the treatment-emergent adverse events in 2 or more subjects. Constipation was reported in 3 subjects, diarrhea in 4, vomiting in 2, fatigue in 4, somnolence in 2 and irritability in 2, contusion in 3, gastroenteritis-viral in 2, nasopharyngitis, cough, rhinorrhea and decreased appetite all in 2 subjects. Next slide, please. The overall or total scores on the PTHS-specific efficacy measures were statistically significant at a p-value of less than 0.05 in the completers or MITT population and in the ITT population, which includes those that were discontinued and had a post efficacy baseline -- or post efficacy measure to report. The mean CGI-I was 2.6 with a median of 3.0 and the mean CIC was 3.0 with a median of 3.0. Again, all 4 PTHS-specific endpoints were statistically significant in both populations. Next slide, please. A bit more about the PTHS-specific CGI-I and CIC measures. In both of these measures, a score of 1 is very much improved and a score of 7 is very much worse. Best practices were followed in this study, and all clinician raters completed calibration training as well as to score and interpret the anchors provided. Training was performed at study start-up and again, during the study. For the clinical global impression of improvement, clinicians give an overall score as well as scores for each domain listed below. For the caregiver impression of change, caregivers give an overall score and score each domain. They're also asked to identify the one symptom area that has influenced his or her rating of the child's overall function. You will see that the domains are very similar for the first 7 domains and that the wording is slightly different to aid in caregiver interpretation and that there are 2 additional domains for caregivers, which include seizures and cognitive abilities or ability to learn. Next slide, please. On the left-hand side of this slide is the waterfall plot of the clinical global impression of improvement in the MITT population. On the Y-axis is the score from very much improved at the top to very much worse at the bottom. The mean score was 2.6 and 9 out of 11 children showed improvement with 1 being very much improved; 4 being graded as much improved, and 4 being graded as minimally improved, and 2 were reported as having no change. On the right-hand side of the screen is the forest plot of the mean CGI-I domain scores. You'll see that there is an overall trend towards improvement, most notably in social interaction, learning and cognition and gross and fine motor. Next slide, please. Here is the PTHS-specific caregiver impression of change. The waterfall plot on the left here shows again the overall scores by subject. 4 patients were rated as much improved by their caregivers and 4 were rated as improved, 2 is unchanged and 1 participant was rated by their caretaker is worse. On the right-hand side is the forest plot showing the domain scores. And again, there's a trend towards improvement, which is most notable for social interaction, motor abilities and communication. Next slide, please. 6 of the 11 subjects showed a 1 point improvement on the clinical global impression of severity score. The caregiver top 3 showed that the overall trend towards improvement, most notably in challenging behavior, language and communication and fine motor. You will note that the air bars are outside of the figure for GI. This is because this was noted for 2 patients only, and they had very disparate results. Next slide, please.. Here are some examples of the clinician notes for the PTHS-specific caregiver impression of change of the -- and the caregiver notes from the caregiver impression of change, sorry, at the end of treatment. This is to provide some additional context to the results in addition to the data reported.

Okay. Thanks a lot, Liza. So I think just going back to these testimonials. I'm not going to read them out, but please have a read of them in your own time because, again, that's what it's all about, and you see these sort of improvements happening. So I'm now going to talk about the opportunity in front of us and I think 2591 more broadly. So first of all, let's talk about Pitt Hopkins. So I think as you know, with all our indications, there are 2 measures of the number of patients. There's the potential theoretical number of patients from prevalent studies that have been done. And then there's the number of diagnosed patients. And you know there's a gap because historically, there's been a lot of misdiagnosis and no diagnosis. It's the same with all our indications from Rett onwards. So for Pitt Hopkins, the potential number of patients, 6,000 to 7,000 in the U.S., which is pretty similar to Rett. I think you probably remember, 6,000 to 9,000 and it's about 1/3 of the Phelan-McDermid potential prevalence. So smaller than Phelan-McDermid, similar to Rett. And on the diagnosed patient side, again, if the ratio is the same against Phelan-McDermid syndrome is about 1/3 of the currently diagnosed patients, both of them lower than Rett. But as you know, that's -- we've said before, that's partly because no one's ever done anything in these things before. So -- and Rett certainly wasn't at the level it is now when we started all that time ago. So we expect this to rapidly increase. And if you look for Pitt Hopkins, there was a census initiated only back in Q1 2023 and already there are 1,400 patients on that census and it's increased by 30% in one year. So we're very confident this is going to increase rapidly. Out of that number, there are about 500 in the U.S. and Canada and the rest internationally. So again, it's about 1/3 of the number for Phelan-McDermid syndrome. There's been a lot of misdiagnosis in the past between probably 3 of our indications, Pitt Hopkins, Rett and Angelman in particular, a lot of sort of simplistic diagnosis is autism. So we think that the whole landscape is shifting here. Genetic testing is improving, a better understanding of autism being many different things. So we do expect these numbers to increase rapidly. And we'll be part of that because one thing that makes it increase is the prospect of a treatment and the noise that, that creates in the community. So we're really excited about this indication. I mean if you've heard me talk before, you'll say and out of our 4 indications, they sort of split into 2, really, Phelan-McDermid and Pitt Hopkins syndrome, we really are leading the way. This -- there's nothing else -- anywhere near where we've got to, whereas Angelman and Prader-Willi are quite different. There's quite a lot of competition there. So I've always favored Phelan-McDermid, Pitt Hopkins as fantastic opportunities for us because they're very like Rett was when we started. And if we can be successful, we really can own those indications, we think. So at the moment, there's one other products in Phase II, but it is focusing purely on the GI symptoms of Pitt Hopkins syndrome. And we're certainly the only people we've done -- we've now done a multicenter trial in the U.S. under an IND supervised by the FDA. We've got orphan drug designation in both U.S. and Europe. This program would be eligible for a rare pediatric disease priority review voucher. And we're really excited about the results we've got in this Phase II trial, and so I can't wait till then to move this program forward. So beyond Pitt Hopkins, let's just talk about 2591 more broadly. So why do we think this is going to be a multi-indication opportunity and it comes down to the mechanism of action. So what we're trying to do here is improve the functioning of IGF-1 in the brain, and IGF-1 plays a critical role in both the formation of new connections between brain cells or synapses and the maintenance of the existing ones, and that's critical for normal functioning of the brain. And it's not happening properly in all of these neuro-development disorders. NNZ-2591, we know the mechanism of action it competitively binds with the binding proteins in the brain, so it should be able to release more IGF-1 to be -- or to be bioavailable to do its job in the brain. That's why we think this ought to have application across different indications, it's not specific to one genetic mutation. All of these syndromes have this similar problem in the brain. So that's why we believe it should be a multi-indication opportunity. So we've now got 2 clinical trial results, Phelan-McDermid syndrome and Pitt Hopkins syndrome, and they are strikingly similar. So on the safety tolerability side, very happy with the profile. It's very similar in both indications. There was one serious adverse event in the Phelan-McDermid trial, which was unrelated to drug. There were none at all in the Pitt Hopkins trial. The 2 global endpoints that are specifically designed for these indications. So even though they're both called the CGI and the CIC, they are specific to each indication. They have different anchors and have been specifically anchored into those syndromes. Very similar result, 2.4 average in Phelan-McDermid, 2.6 in Pitt Hopkins, 2.7 and 3 for the CIC and the vast majority of patients showing improvement. So very similar outcome there. And then the CGI-S and Liza didn't talk too much about this, but the CGI-S is actually more difficult to move, particularly in a 13-week study. It's quite unusual to be able to move a level on the severity of the disease, even if you're showing an improvement on the CGI-I. So we're really excited that we've actually shown that in both trials, and have 7 patients in Phelan-McDermid, 6 in Pitt Hopkins have actually moved an improved level of severity in their condition. And then finally, the syndrome-specific efficacy measures in both studies were all statistically significant changes from baseline. So again, a very similar outcome. So we certainly feel this does validate our multi-indication strategy. So very happy with where we sit today. So I want to come back now to this challenging protocol that I started this discussion on. And now we're seeing the safety data from the Phelan-McDermid syndrome and Pitt Hopkins syndrome trials, then we absolutely believe that we shouldn't need that protocol, it really should support reviewing and optimizing that protocol. And unfortunately, that protocol is being used in the Prader-Willi syndrome trial because, of course, we started that trial without this data. So we certainly feel that we shouldn't be proceeding with the Prader-Willi syndrome trial under this protocol, but unfortunately, you've got to have the FDA's agreement to that. So we do intend to do that. I think it's not fair on the patients and their families to put them through this protocol. I mean, there just isn't so we need to reduce that burden on them. And the other issue we have with Prader-Willi syndrome is it is different to the others in all the other 3 trials, which have all had this difficult protocol. There were no other trials that the people could go into whereas in Prader-Willi syndrome there are. So there are other trials that don't have that burden and are also offering long-term open-label extensions beyond the study as well. So we're not competitive against those other trials. And the other important thing is if we can rationalize and change this protocol, then of course, we can use it in other indications, which we are busily working on in the background. So today, we have paused the Prader-Willi syndrome Phase II trial, pending -- relooking at that protocol, but we're not going to do that until after the end of Phase II meeting with the FDA that we're having for Phelan-McDermid syndrome in Q3. So that will be when all the safety data is presented to the FDA. And so we'll relook at the protocol subsequent to that. And the other factor here is that, as I mentioned, we are at the moment doing preclinical studies for other indications. And of course, the beauty of this multi-indication strategy is that we should be able to move straight into Phase II with new indications. So we would certainly intend to do that with an optimized protocol. So there's going to be, again, a lot of decisions to make later on, but it's not going to happen until after the end of Phase II meeting with FDA. So I think in closing, just to summarize where we are with 2591. So we've positive results now in 2 indications, which we're so pleased about and then, of course, we've got another result coming. So in Q3, we'll get the result from the Angelman syndrome, Phase II trial that's been done here in Australia. We'll also, in Q3, have our end of Phase II meeting with FDA for Phelan-McDermid. That's really important. And just a bit of extra information, so Pitt Hopkins and Phelan-McDermid are in the same division of the FDA. So that's the Division of Neurology, whereas Angelman syndrome and Prader-Willi are in psychiatry. So I think that, that meeting on Phelan-McDermid syndrome is going to be really important. The endpoints that we're talking about using very similar in that and Pitt Hopkins that will give us, I think, great information for Pitt Hopkins as well when we have that meeting. Of course, the mechanism of action relevant for many others. And as I said, we're working on those in the background now. And then the final bit of potential upside for us in 2591, of course, is that Acadia has the rights to Rett Syndrome and Fragile X syndrome. And we get the same economics from them as we do for trofinetide if they choose to proceed with that. It's their decision whether they do or not, but I'm hopeful that they will. And that, again, will be a great upside for us even if it's not the main game for 2591. So that's the end of the presentation. Thank you for listening. I will now move to Q&A.

And we will start with questions that came in for the webinar. So the first one is, can you please update us on the potential Phase III clinical trial in Phelan-McDermid syndrome. Does this trial result change the setup of a trial? Will you now seek to include Pitt Hopkins patients in the trial? And if so, does it change in Neuren's appetite for licensing for 2591? So a couple of different questions in there. We're not going to combine patients in these populations into the trial. If -- I mean, I think even though the results are similar on the headline level, the populations are very different and Pitt Hopkins kids, much more complex and impaired, so it's not the right thing to do to combine them into a trial. About changing our appetite for licensing. It doesn't really change anything on that. I mean I've always said that we could comfortably execute and fund 2 indications ourselves that hasn't changed, but we need to meet with the FDA first before deciding any of that. Next question, could you please expand on the self-harm adverse event mentioned in the announcement in relation to one patient? And any significance related to this. So this is, I think, one of the discontinuations Liza, who had multiple different things, but one of them I think is self-harm. I think that's what he's referring to. Do you want to just make a comment on that?

Sure. Self-harm is actually not unusual in Pitt Hopkins syndrome. So this is not necessarily a surprise, and certainly, for adverse event reporting, if an existing event gets worse then it will be reported. And this child also had abdominal distension and constipation. So these may contribute.

Thanks. And along with similar lines, can you provide more detail on the safety element. Trying to frame the 4 discontinuations, why would they discontinue with no SAEs. Can you comment on the efficacy profile in those 4 patients. So I mean people don't only discontinue for SAEs, and I've talked about the complexity of this protocol and had multiple things something here. But Liza, do you want to make a comment on the safety side of it before we get to the efficacy?

I think on the safety side, Jon, you're absolutely right that this is an arduous protocol for families that are already dealing with a lot. And so there may be a lower threshold for discontinuation. Obviously, the 2 unrelated events we're sort of acute in nature and likely due to illness, and the other 2, I think, the adverse events in the one subject while they were mild, again, the demands of the protocol and the overall demands of the disease that may have just tipped the balance in favor of leaving the study.

Thank you. And then the other part was the efficacy profile of those 4 patients. So we haven't included them in the main analysis because they don't have the same measurements at the same time necessarily, but we have shown you that if you include them, it doesn't affect the statistical significance of the result. So that's important. I mean, all I'll say on that is that there was a range of outcomes in those people for the measurements that were taken, some improved and some didn't. Okay. That was the pre-submitted questions, let's got to the Q&A. Right. Are there any key clinical differences between Pitt Hopkins and Phelan-McDermid syndrome that would explain a slightly different adverse event profile we have seen between each respective trial? Noting that constipation was more prevalent than in the past, albeit at the end is very small. Liza, do you want to comment on that?