Morning, all. Welcome to Neuren's investor webinar on the phase 2 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 John Pilcher, CEO, and Liza Squires, Chief Medical Officer. John and Liza will make the presentation today, then all of us will be available for a Q&A session following the presentation.
You can use the Q&A button at the bottom to submit your questions. 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 John 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 trial, phase 2 trial of NNZ-2591 in Pitt-Hopkins syndrome.
And the way today will work is I'm gonna 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 wanna start by just talking a little bit about Pitt-Hopkins syndrome and about the families and patients that have participated in this trial. You'd have heard me say before that for these phase 2 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, a vulnerable population, so we have to be extremely and appropriately cautious from a safety point of view.
So 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.
You know, 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 own normal lives and other siblings to look after, too. So, you know, I seriously take my hat 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.
You know, 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, you know, they're the heroes of the story in some way. You know, they put their faith in us when no one had seen anything about the drug before. So, you know, I can't thank those families enough.
The challenges with 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 wanna thank the Pitt Hopkins Research Foundation, who've played an important role in this as well, and will 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. So the FFQs measurements that were designed specifically for Pitt-Hopkins. And it's clear to us from the result on this trial that you need these specific endpoints. That, you know, 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 these endpoints that have been specifically designed for the population, and they've worked very well in this study. The last thing I wanna or people I wanna thank is the Neuren team.
So, you know, that no one's 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 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 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 NNZ-2591 basically changed the impaired mice back to being indistinguishable from the wild-type mice. We didn't do quite as much as we'd 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 are, firstly, obviously, given what I just said, safety 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 or safety parameters, and the adverse events, there were no serious adverse events. Nearly all of them were mild. So yeah, 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 assessed by both the clinicians and the caregivers across all four 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, you know, being by chance alone? So very pleased with that outcome. And then more specifically, really pleased with what we saw in the two global measures. The one that's the physician measure, the CGI, and the one that's the caregiver measure, the CIC. So the CGI, mean score of 2.6.
If you remember in the Phelan-McDermid trial, it was 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 was 2.7. So really happy with that outcome. 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 communication, 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 gonna ask Liza now to take you through some of the detail of the trial. Again, we're gonna move quite quickly, so start off with the design of the trial, please, Liza. Over to you.
Thank you, John. Good morning, everyone. This phase 2 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 Medical Center, UT Southwestern Medical Center, University of California, San Francisco, University of Alabama at Birmingham, and Children's Hospital Colorado.
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. 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 three concerns. As John 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. Four subjects discontinued due to treatment emergent adverse events. These discontinuations due to TEAEs that were all mild and moderate and all resolved. Two were unrelated to study drug, one participant with COVID-19 and another with mild vomiting, diarrhea, and lethargy.
2 were 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 1 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 a 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 four 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 one is very much improved and a score of seven 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 startup 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 seven domains, and that the wording is slightly different to aid in caregiver interpretation, and that there are two 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 nine out of 11 children showed improvement, with one being very much improved, four being graded as much improved, and four being graded as minimally improved, and two 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's 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 as unchanged, and 1 participant was rated by their caretaker as 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 three showed that the overall trend towards improvement, most notably in challenging behavior, language and communication, and fine motor. You will note that the error 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. Next slide, please.
Here are some examples of the clinician notes for the caregiver, for the PTHS-specific Caregiver Impression of Change, 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 gonna read them out, but please have a read of them in your own time, because, again, that's what it's all about when you see these sort of improvements happening. So I'm now gonna talk about sort of 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, you know, with all our indications, there are two 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.
You know, there's a gap, because historically, there's been a lot of misdiagnosis and no diagnosis. You know, it's the same with all our indications, from Rett onwards. For Pitt-Hopkins, the potential number of patients, 6,000-7,000 in the U.S., which is pretty similar to Rett, which if you remember, is 6,000-9,000, and it's about one third of the Phelan-McDermid potential prevalence. So smaller than Phelan-McDermid, similar to Rett.
On the diagnosed patient side, again, it's the ratio's the same against Phelan-McDermid syndrome. So it's about one third of the currently diagnosed patients, both of them lower than Rett. But, you know, as you know, that's, we've said before, that's partly because no one's ever done anything in these things before.
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, you know, 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 gonna increase rapidly.
Out of that number, there are about 500 in the U.S. and Canada, and the rest internationally. So again, that's about one third of the number for Phelan-McDermid syndrome. There's been a lot of misdiagnosis in the past between three of our indications, Pitt-Hopkins, Rett, and Angelman, in particular. A lot of sort of simplistic diagnosis as autism.
So we, you know, 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, you know, we're really excited about this indication. I mean, if you've heard me talk before, you'll say, you know, out of our four indications, they sort of split into two really. Phelan-McDermid and Pitt-Hopkins syndrome, we really are leading the way. 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, I've always favored Phelan-McDermid and 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 product in phase 2, but it is focusing purely on the GI symptoms of Pitt-Hopkins syndrome.
And you know, we're certainly the only people. 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, you know, really excited about the result we've got in this phase 2 trial, and so can't wait to then move this program forward.
So beyond Pitt-Hopkins, let's just talk about 2591 more broadly. So, you know, why, why do we think this is gonna be a multi-indication opportunity? And it, it comes down to the mechanism of action. So, you know, you know, what we're trying to do here is improve the functioning of the IGF-1 in the brain.
And IGF-1 plays an critical role in both the formation of new connections between the brain cells or synapses and the maintenance of the existing ones. And that's, and that's critical for normal functioning of the brain, and it's not happening properly in all of these neurodevelopmental disorders. And as of 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. So that's why we think, you know, 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 two 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 two 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, you know, 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, you know, 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, you know, 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.
So we're really excited that we've actually shown that in both trials. You know, 7, 7 patients in Phelan-McDermid, 6 in Pitt-Hopkins, have actually moved and improved their level of severity in, in their condition. And then finally, you know, the syndrome-specific efficacy measures in both studies were all statistically significant changes from baseline.
So again, the very similar outcome. So we certainly feel this does validate our, you know, 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 you know, now we've seen the safety data from the Phelan-McDermid syndrome and Pitt-Hopkins syndrome trials, then we absolutely believe that we shouldn't need that protocol. You know, it really should support reviewing and optimizing that protocol.
Unfortunately, that protocol is being used in the Prader-Willi syndrome trial because, of course, you know, 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, you know, it's not fair on the patients and their families to put them through this protocol. I mean, it 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 three trials, which have all had this difficult protocol, there were no other trials, you know, that people could go into. Whereas in Prader-Willi syndrome, there are.
So, you know, there are other trials that don't have that burden, and are also offering, you know, 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 2 trial, pending relooking at that protocol. But we're not gonna do that until after the end of phase 2 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, you know, 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 Two with new indications. So we would certainly intend to do that with an optimized protocol.
So there's gonna be, again, a lot of decisions to make later on, but it's not gonna happen until after the interface meeting with FDA. So I think in closing, just to summarize where we are with two five nine one. So, you know, we've positive results now in two 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 2 trial that's being done here in Australia. We'll also, in Q3, have our end of phase 2 meeting with FDA for Phelan-McDermid. That's really important. Just a bit of extra information: 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 meeting on Phelan-McDermid syndrome is gonna be really important. The endpoints that we're talking about using, very similar in that and Pitt-Hopkins, so it 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 great upside for us, even if it's not the main game for 2591. So that's the end of the presentation. So thank you for listening. I will now move to Q&A. And we will start with questions that came in before the webinar.
So the first one is: Can you please update us on the potential phase 3 clinical trial in Phelan-McDermid syndrome? Does this trial result change the setup of the trial? Will you now seek to include Pitt-Hopkins patients in the trial? And if so, does it change Neuren's appetite for licensing for 2591?... So a couple of different questions in there.
We're not gonna combine patients in these populations into a trial. Funnily, even though the results are similar on, you know, the headline level, the populations are very different and, you know, 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 two indications ourselves. That, you know, 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, was self-harm. I think that's what he's referring to. Do you want to just make a comment on that?
Sure. Sure. Self-harm is actually not unusual in Pitt-Hopkins syndrome, so this is not necessarily a surprise. And, you know, 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, these may contribute.
Thanks. And along with similar lines, can you provide more detail on the safety element? Trying to frame the four discontinuations, why would they discontinue if no SAEs? Can you comment on the efficacy profile in those four patients? So, I mean, people don't only discontinue for SAEs, and I've talked about the complexity of this protocol, and we had multiple things happening here. But, Liza, do you want to make a comment on the safety side of it before we get to the efficacy?
Sure. I think on the safety side, John, you're, you're absolutely right that this is an arduous protocol for families that are already dealing with, with a lot. And so, there may be a lower threshold for discontinuation. Obviously, the two unrelated events were sort of acute in nature and likely due to illness.
And the other two, I think, you know, the adverse events in the one subject, while they were mild, again, the demands of the protocol and the overall demands of the disease, it may have just tipped the balance in favor of leaving the study.
Thank you. Then, the other part was the efficacy profile on those 4 patients. So, you know, we haven't included them in the main analysis because they, they don't have the same measurements at the same time necessarily. But we have, 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, all I'll say on that is that, you know, there was a range of outcomes in those people for the measurements that were taken, and some improved and some didn't. Okay, that was the pre-submitted questions. Let's go to the Q&A. Sorry, just excuse me a minute. Excuse me.
Right, are there any key clinical differences between Pitt-Hopkins and Phelan-McDermid syndrome that would explain the slightly different adverse event profile we have seen between each respective trial? Noting that constipation was more prevalent than in the past, albeit the N is very small. Liza, do you want to comment on that?
Certainly, Pitt-Hopkins syndrome is, by and large, is more severe, so the GI effects are more severe. As we also showed, the developmental disability is more severe as well. So in general, I think this is a more complicated, medically involved and neurodevelopmentally involved population, and that may be contributing, in some degree, to, to what we have seen. But again, the n's are small.
Thank you. And then next question: How do you know that the dropout due to mild vomiting, diarrhea, lethargy was not study drug-related? Yeah. Liza?
Sure. So in this case, the relationship to study drug is determined by the investigator. This occurred shortly after study drug initiation and, you know, was felt to be unrelated. And given the combination of vomiting and diarrhea, I would expect that this may have been infectious of one type or another in nature. But that's just my assumption. But it was indeed mild, and I think just unfortunately happening at the beginning of the study, the family opted out, but the investigator did not feel that this was related to drug.
And maybe just to emphasize that, in case people don't know, it's not Neuren that decides whether it's related or not, it's the investigator, you know, at that site who makes that decision. Next question. Thanks for the presentation. What does the potential optimized new protocol for Prader-Willi look like in comparison to the existing phase 2 protocol?
And would we expect this to be the protocol for the other disease indications, should they progress from preclinical? So look, that revised protocol doesn't exist at the moment. As I've said, we're not gonna do that until after we've met with the FDA in Q3. However, I'll just mention a few things.
You know, one thing that's made this very challenging is having to start with an older age segment within the population and check the safety before moving to a younger segment, and then a younger segment. Having, you know, a review of the safety data at each stage, that was very onerous, and we would certainly be seeking not to have to do that and to be able to take all comers from day one.
We also had to do, likewise, very careful titrating up of the dose, and again, independent monitoring of safety before for every single patient, or for every single dose escalation. Again, we would hope not to have to do that.
And then the other thing I mentioned, you know, multiple visits to the home from nurses, as well as visits to the clinic. So again, we would be looking hopefully to, to reduce that burden. But, as I said, you know, the, the detailed protocol doesn't exist yet, and we'll be working on that, in due course. Okay. If you can comment with respect to Prader-Willi syndrome, how do you see Soleno Therapeutics' market cap at $1.5 billion in Neuren's against Neuren's multitrial opportunities?
Oh, look, not gonna comment too much on other companies, but, the only thing I'll say is it, it does show you the, the value that we put on a single drug for a single indication, that's not, not approved yet. And, you know, we saw...
It's been talked before about Biogen's acquisition of Reata, which again, was a single drug for a single indication in a rare disease. You know, very high valuation put on that once it was approved by the FDA. So, so yeah, yeah, there's certainly big valuations out there for single drug, single indication in rare disease. And we, we hope we've got more than that, but, I can't say any more than that, really. Next question: Has the Angelman trial completed?
Yes, it has. When will the FDA meeting be held? As we said, Q3. I'm not gonna narrow that down anymore. It's in Q3. Next question. Congrats to the Neuren team on another impressive result. Thank you very much. Could you please elaborate on what other indications for NNZ-2591 may be commercially attractive?
Also, could you advise, when would you plan to have an end of Phase 2 meeting on Pitt-Hopkins with the FDA? So I'm not gonna give any details on the other indications that we're looking at. I've said before, you know, that our focus is gonna be on orphan indications, given the difficulty of mixing orphan and non-orphan, so you should expect them to be orphan indications. I'm not gonna give any more on that yet.
That will happen in due course. FDA meeting on Pitt-Hopkins. Yeah, we haven't... You know, we've only just seen the results. We've been heads down in the results and still have some more analysis to do. So we don't know yet when we'll meet with the FDA. So we'll advise that in due course.
I'm gonna come back to that because I really want to focus on questions that are related to 2591, which that one isn't. I'll come back to that if we have time at the end. Just to understand, the Prader-Willi syndrome pause is to determine whether there is need to subject participants to burden just for a further safety review for 2591.
So I think what we're saying is, you know, we all of these four studies started with the same protocol because at that stage, we didn't have any safety data to be able to justify to the FDA of not having that protocol. Now, we have. So it's very if we were gonna start the Prader-Willi syndrome trial today, we certainly wouldn't be proposing the current protocol.
We would be proposing something quite different. It's not fair to subject the participants to this burden when that's the case. That's why we're gonna—that's why we'd intend to change it. You have shown the baseline for CGI being five, so that's CGI-S, not CGI-I. What was the baseline score of CIC patients? Yeah, so slight misunderstanding of the measures here. CGI-I and CIC are changes from baseline.
They're not a baseline score and an end of treatment score, and then subtracting to get the difference. They are a score that is a judgment of whether the patient has improved. The CGI-S does have a baseline and does have an end of treatment score, and so it was the baseline CGI-S score, which was five, indicating the severity of the syndrome.
And so once you get to the end of the treatment, then you'll see the reduced scores on the CGI-S. Next question: Can you be more specific on what this protocol entails? I'm a little bit puzzled by that, because I think I pretty much talked about that at the beginning of the webinar.
So unless you missed the beginning of the webinar, which I guess is possible, but it's, you know, horrendous complexity, multiple visits to site, multiple visits from home nurses, multiple medical procedures, examinations, blood draws, which are not easy in this sort of population, and they wouldn't be easy in a normal population, let alone this population. Can you comment about the diarrhea incidents compared to PMS or DAYBUE?
How would you rate the impact of diarrhea on caregivers? Liza, this relates to Daybue, so I'm gonna answer it. So I think there was no real difference, compared to Phelan-McDermid syndrome, other than I think, Pitt-Hopkins kids have worse GI issues than PMS kids. It's more of a problem and more constipation. So it's very different to Daybue.
We don't think there is any impact of the drug on diarrhea, so we think it's very different to that. Based on the results today for Pitt-Hopkins, could you discuss what could be good likely endpoints to use in a registration trial? Did you see any age-specific differences in outcomes in the trial? Liza, would you like to answer those two separate questions?
Sure. Obviously, we're still looking at the data with respect to age differences, so more to come on that. And, you know, at first blush, obviously, we're looking very seriously at the Pitt-Hopkins specific measures, as they are sensitive to change and demonstrative of what's important to families with the disorder.
Thank you. When are we likely to be informed about the other preclinical indications you're looking at? So look, for competitive reasons, it's not gonna be until we're ready to move forward into phase 2 trials. So, it's gonna be some months. I'm not gonna specify how many yet. We'll just let you know as soon as we can.
How confident are you that the FDA will approve the Pitt-Hopkins syndrome-specific endpoints that you've used in this trial, given the other secondary endpoints you used in this trial for other neurodevelopment were not statistically significant? So I'll ask Liza to come in in a second. Just what I would say is, in a way, Pitt-Hopkins is no different to Phelan-McDermid syndrome here.
You know, even though there were other endpoints that hit on Phelan-McDermid syndrome, they're not what we believe are the right primary endpoints for a registration trial. So actually, you know, it's a very similar situation in both trials. Liza, anything else you want to add to that?
No, I, I agree. I think that the concordance we're seeing between, you know, the caregiver top three and the domains that are used in the CGI-I and the CGI-S, as well as the CIC, really speak to the overall impact of the syndrome, rather than focusing on one specific aspect, such as only GI or only sleep.
And I think the other point I'd make is that I think, you know, we're confident that they... We saw a positive outcome in all of them. You know, if we'd only hit on one and not on the other three, then you might be starting to question it, but we hit very consistently on all four, so. Next question. I'm glad this has been asked, 'cause I meant to mention this too in my comments.
Could you remind us how many of the endpoints that were looked at in the early Rett syndrome trials, disease-specific or not, have been positive as compared to Pitt-Hopkins, for example? Great, great question, because I was gonna say that actually this is quite similar to Rett. I think it's the Phelan-McDermid syndrome trial that's the outlier here.
I mean, that was extremely unusual to hit on all those endpoints. In Rett, I mean, I think in the second phase 2 trial, I think we had 5, core efficacy endpoints, and 3 out of 5 of them were positive. And in the first Rett trial, I think we had, well, we didn't have any that had P equals 0.05, less than 0.05, but we had, two and two endpoints in particular that looked good, but a lot of the others didn't show anything on.
So actually, this result is more similar to the Rett results, and in a way, it's not surprising, because Rett and Pitt-Hopkins, out of all of these indications, are probably the most similar to each other. What's another question not about, two five nine one?
I'm also conscious we've got an AGM tomorrow, so if you're asking corporate questions, I think that's the right time to be asking those questions. Given the two positive results so far, are you now more confident with the Angelman result? So look, I suppose, you know, it does increase our confidence further that the drug works and that the mechanism of action is valid and things.
So that increases our confidence, but to say the same thing as I said before, the Pitt-Hopkins result, all of these things are different, the conditions are different, different sites, different investigators, different measures, albeit the same scoring system, but different anchors. And there's another difference with the Angelman study that's been done in Australia, not in the U.S. That's another difference. So, you know, there are always differences in trials.
You can never be sure, but, you know, we obviously, obviously feel good about the drug and, and what it's doing. When you say due course for additional indications, do you have an approximate time frame and we will know? Sorry, I'm not gonna give that yet, I'm afraid. Okay, I think I've already answered that. It's asking about what changes we're proposing to the Prader-Willi protocol.
Are there any differences in translating the successes from Phelan-McDermid syndrome, Pitt-Hopkins syndrome to Angelman? So I think and hope I've answered that. There will, we do have the similar, you know, there'll be Angelman-specific efficacy measures in the Angelman trial, so there is a sort of a point of comparison, but, we're not much more I can say on that. What level of data from this trial would be shared with Acadia on NNZ-2591?
Is there any discussion on them wanting to develop 2 5 1 1 for either Rett or Fragile X? So I don't think you'll be surprised to hear me say I can't say anything about that. It's confidential. It's up to them, but of course, we collaborate very closely, and they have every right to see data that could impact their development.
So I'm sure we'll certainly be discussing it with them. How many patients have already enrolled in the existing Prader-Willi syndrome trial, and are they on pause, too, at the moment as the protocol is being revised? I'm not gonna give any details other than to say that there aren't any patients who are, you know, who are on the trial, that we're gonna have to stop this. We're not in that situation.
Eleven children tested, seems like a small sample. Is this normal? So then, you know, that was 11 completers. All of these trials, we started saying we wanna enroll up to 20 kids. It is a small sample size, but it's not unusual in an exploratory first trial in patients in rare diseases to be doing that sort of thing. Again, this is a very different situation to a placebo-controlled phase 2b trial, looking at multiple doses in a bigger population.
It's a completely different situation to that. So this is certainly not unusual in this setting. And I think, you know, one thing I'll also say is, to get statistical significance is much harder with smaller numbers. The more numbers you have, the easier it is to get statistical significance.
So actually, we're pretty happy that we got it with only 11 patients or, or with, 15 patients, whichever way you look at it. What is the soonest you would estimate you could get up and running with a different Phase 2, Phase 2 protocol? Again, I think I've said, we're not gonna do it until after the, meeting with FDA in Quarter Three, so it'll be after that. What takeaways are we expecting from the FDA meeting in Q3? So, look, we want, we, we hope for clarity about the way forward. So we're gonna, we're gonna propose what we want to do to move towards registration, what studies we think we should do.
There's a huge amount of detail that goes behind that, with all our justifications, and we'll hope for some clarity out of that meeting of the way forward. You also go into these meetings with other alternatives in your back pocket. And there's usually plenty of discussion on a variety of things, but that's what we're hoping to get out of the meeting.
So I think that's it. Oh, no, it was it. There's another one coming, but I think I've answered that. When are you aiming to meet FDA on Pitt-Hopkins phase 3 trial? Yes, it's too early for me to answer that. We haven't determined that yet. Will we be able to go straight to a registration phase 3 trial with these results, or will we need a phase 2b trial? Look, the...
Again, we need to meet with the FDA to know all of this. We don't intend to. Often with phase 2b trials, what you do is dose ranging. You know, you might have multiple doses, and you're still trying to work out what the right dose is for a phase 3 trial. We don't intend to do that. We think we've got the right dose in all of these trials, so there wouldn't be a need to look at doses.
Often in rare disease, you get a situation where it might be a phase 2/3 trial, and you might have a look at, you know, some of the data as you go through the trial. Is that a possibility? Maybe. Could we go straight to a typical registration trial? Maybe.
Again, we've only just looked at the result. We'll be working out all of that before we meet with the FDA and getting clarity from them. Sorry, I keep thinking we're finished, but they keep coming in. Now that there are two Phase 2 indications, statistically significant. This is asking about takeover offers. Yeah, I'm sorry, I'm not gonna answer that.
I think we've got AGM tomorrow. If you want to answer the last sort of corporate questions, let's hold that for tomorrow, please. So I think that's it. Thank you. And in fact, it's 11:55 A.M., so we've been going nearly an hour, so let's stop there. Many thanks to you all for listening to us. Great morning.
We're all feeling very happy, and I hope you are too. Thanks to everyone who participated, and we'll look forward to speaking with you soon. In fact, many of you tomorrow, probably at the AGM. Thanks a lot. Bye.