Neuren Pharmaceuticals Limited (NEU) Earnings Call Transcript & Summary

Good morning, and welcome to Neuren's investor webinar to discuss our recently announced business updates. My name is Gerry Zhao, Chief Business Officer at Neuren. Joining me today on the call are -- Patrick Davies, Chairman; and Jon Pilcher, Chief Executive Officer. Patrick and Jon will present followed by a Q&A session. [Operator Instructions] Before we begin, please note that today's webinar will include forward-looking statements, which are subject to risks and uncertainties that may lead to different outcomes. I'll now hand over to Jon to commence the presentation.

Thank you, Gerry. Good morning, everyone. Thanks very much for joining us today. So here's the agenda of what we're going to go through. So in a minute, Patrick will start with some comments about the share buyback program that we announced last night. Then I will just give a recap on the 4 items of news from last week and give a little bit of extra commentary around those. And then I'm going to finish by just a recap on our overall strategy for 2591 and why we're prioritizing what we are prioritizing. So there's a lot to get through. We obviously want to leave some time for questions. So we'll move quite rapidly. And when we come to the Q&A, depending on the time, if we're struggling for time, then we will prioritize questions that are relevant to this content today. So let's get going. I'll pass to Patrick, please, to just talk about how we, as a Board, have thought about things before activating the share buyback.

Great. Thanks very much, Jon, and good morning, everybody. Thank you very much for joining us today. It's great to see so many people interested in our company. As you'd be aware, yesterday afternoon, the Board approved a new on-market buyback program of up to 5% of the shares on issue. Neuren is in an enviable position for a biotech company in this country, and we are very confident in the prospects of further success ahead of us. We have a very strong cash position, supported by growing cash flows from the DAYBUE franchise. Neuren's NNZ-2591 development programs for Phelan-McDermid syndrome, Pitt Hopkins syndrome and HIE all are and will remain well funded alongside the buyback. Our pivotal trial for Phelan-McDermid syndrome is underway, and we have clarity on the path ahead for Pitt Hopkins syndrome and HIE. We have the financial resources to confidently execute our plans, and we remain bullish about the shareholder value creation that Neuren can deliver. Our strong financial position gives us the ability to initiate the new buyback and the progress the team have made to date gives us increasing confidence about the future. The Board views the current share price as materially undervaluing Neuren's assets relative to our internal analysis and also to the range of recently published analyst valuations. This is hardly news to all of you, but the share market is extremely volatile at the moment, and many companies are seeing large share price movement. That said, the movement in our share price last week was clearly disproportionate to the valuation impact of all the news flow, and we are interrogating the reasons for that. There are 8 research analysts covering Neuren. And after updating for the news flow, they have an average valuation of USD 24.40 per share, and all of the analysts have a buy recommendation on Neuren. Ladies and gentlemen, we are very grateful to all our supportive shareholders, and I can assure you that we will continue to evaluate all options to maximize shareholder value. Jon, for the moment, I'll hand over to you.

Thanks very much, Patrick. Okay. So let's get into the news of last week, and I'm going to take it in the order that it unfolded. And of course, it was very unusual that it all fell in a single week last week. And potentially, that was unhelpful, but that was completely out of our control, obviously. So let's start with the thing that came first, which was the Trofinetide European regulatory update. So I'm going to do three things here. I'm going to just make sure we will understand the process from here. Then I'll give some comments from my point of view, and then I'll make a comment about Acadia. So the news was that Acadia were informed of a negative trend vote in inverted commerce by CHMP. So just a little bit of explanation around that. So the CHMP is the committee of the EMA that makes the decision to either approve or not approve the drug. So it is a committee, so it's a majority vote. And what happens is that when you have an oral explanation as Acadia had, they have an informal vote after that explanation, and that's this trend vote. And so that was a negative majority vote by the committee following that. So then what happens is at the next meeting, which is at the end of February, the formal opinion will be adopted by that same committee. Now if that formal opinion follows the trend vote and is negative, then Acadia has already said that they're going to request reexamination of that opinion. They have 15 days to request that. And then when they request that, they then have 60 days from the date of the opinion to provide their grounds for why it should be reexamined. And then the CHMP has another 60 days to reexamine the opinion. Now again, important to understand as well the CHMP committee are not the people who do the review. They are a committee that makes a decision based on the review that's been done by others. And that review is led by so-called rapporteurs. 2 people are appointed from different countries within the EU to conduct that review. So something very important to understand is that, that reexamination, they appoint different rapporteurs to conduct that. So you've got different people looking at it, and I think that is very important. You're not just trying to convince the same people again. So that's the process that's going to unfold. So I'm going to make some comments now, and this is from me. I'm not speaking from Acadia here about where we've got to hear now. It might surprise you to hear me say, I think this is a really bad outcome for the Rett community in Europe, most importantly. When you think the drug has been on the market in the U.S. now for 2.5 years, we've got more than thousand patients on the drug, more than 300 contributing real-world data to Acadia's formal LOTUS study collecting all that real-world evidence. It's been approved by the U.S., Canadian and Israeli authorities based on exactly the same data. So I do think it's a very bad outcome so far. I think what we need here is for someone and I guess, the committee to take a holistic view of all the available evidence here. I mean that's what's needed here, not just looking at the clinical trial data from years ago, but really taking a holistic view. So that's very much my hope that that's what can happen with some new people involved in the review. And then the final comment I'll make, as I said about Acadia. I mean, Acadia, there's so much incentive here. I mean they've paid us a lot of money to expand their rights from the U.S. to the world. They've made a big investment in establishing their initial commercial infrastructure in Europe for the first time. And you'll have seen the words from Catherine in [Acadia's] announcement, I think she said many of the things that I've just said. So I really think Acadia is going to put absolutely everything into the remaining part of this process. I fully support them in doing that, and we hope we're going to get the right outcome here. So that's it on that topic, and I'm going to move on, except that I want to just make the point, again, the reaction to this last week, way out of proportion to the valuation impact to us because -- the main thing for us remains the U.S. plus the international named patient programs that are going on in Europe, in the Middle East, in South America. So just to remind you that on the 26th of this month, Acadia will have their Q4 and full year earnings call. So we'll hear how the Q4 turned out. And remember that the guidance for the year from Acadia was for net sales between USD 385 million and USD 400 million. And that means that the guidance from us for our royalties based on that is between AUD 63 million and AUD 66 million for the year. And remember, that's 100% margin to us. There's some really encouraging things even in the very recent communications from Acadia, the long-term persistency, so at 12 months, the number of patients who are still on treatment after 12 months continues to trend upwards. It's now up to 55% from 50%. And we certainly think that can keep improving. It's our Neuren's view that a patient starting today has got a much better chance than that staying on treatment longer term. And so therefore, mathematically, that has to keep rising we think. Really important thing coming as we speak is the launch of DAYBUE STIX. So the powder formulation of trofinetide as an alternative to the liquid formulation. And just quickly mention, we, as Neuren developed the liquid formulation originally for a very good reason because for the kids, it's a good form to take the drug and many of them are fed by feeding tubes. But this DAYBUE STIX powder really provides something different and additional. So the ability to reconstitute it in whatever flavor, whatever volume suits your child. It also doesn't contain some of the ingredients that are in the liquid, which some families don't like. So we certainly think there's going to be families who haven't wanted to try the liquid who will try DAYBUE STIX. And we're also hopeful that there will be families who discontinued on the liquid that will come back and try the powder. So we're very excited about that launch. I think Acadia [R2], it's going to be a limited basis in the first quarter just in the centers of excellence in the U.S., but then we'll be launched more broadly after that. So we're very excited to see the outcome of that. Before you get too excited, you're obviously not going to see any outcome in 2025 from that. And even in Q1 2026, I think it will be beyond that, but I think that could have quite an impact. So we've put this table out before, but I just want to just again remind you about it of the possible upside there could be in the U.S. So remember, there's three factors here. How many patients are there and it's consistently growing. The latest thing is now at 6,000. So it's reached the bottom of that 6,000 to 9,000 theoretical prevalence. It's just been steadily growing from the 4,500. Secondly, what percentage of those patients can you get to start therapy? And remember that outside the centers of excellence, it's only 27%, a lot less than in the centers of excellence. Big opportunity for Acadia, and that's -- they've expanded their sales force and increased the sophistication of the marketing information that's getting out to those doctors around the world -- sorry, around the U.S. And then the third element is, of course, that persistency rate. And as I said, that's continuing to climb. And this table we've put out before in presentations, we're just assuming conservatively only 50% persistency, so not the higher amount. But if you look at the table, as percentage starting therapy increases as the number of diagnosed patients increases, you can get a very, very significant increase from the number of patients who are on treatment today. So notwithstanding a disappointment about the European position, which we hope can be rectified, it's not the main game. The main game is the U.S. and will continue to be. Okay. So I'm now going to move to 2591. So the second bit of news we had last week, obviously, was the FDA feedback on both HIE and Pitt Hopkins syndrome. And before I get to the specific feedback, I just want to mention something. I know some people didn't like the fact that I -- in the announcement, I winged about the FDA process here. And I want to make it very clear, I was winging about the process, not about the outcome. And I just want to explain why that is because it is important. So the general thing you have with FDA meetings is you meet on a particular day. These days, it's very rare to be face-to-face. It will usually be virtual. A day before, if you're lucky more than a day before, you'll get preliminary comments from the FDA that tells you their thinking. So then you've got a day to digest that, decide what you actually want to discuss at the meeting and you usually home it down to two or three items, and then you might formulate alternatives to what you've put in the original submission. That's such a helpful process and in both the Rett syndrome program and the Phelan-McDermid syndrome program was very helpful to us. So I was very frustrated that we didn't get the opportunity to do that. We just got written responses, which is effectively just like getting the preliminary responses with no ability to discuss anything. Now notwithstanding that, despite that, we actually got a good outcome. So we've got a clear path in both of these indications. So I'll just quickly recap on what the key points on that are. So for HIE, we were proposing to open an IND. It's a pre-IND meeting, and you have to open an IND with a study. And so our proposal was a 1-month study in neonates and infants who have HIE and to look at the PK and the safety in that population. The reason you have to do that is because in all other studies, kids down to 3 years old have had the drug, but not below that. So you have to have a look at that before you launch into a bigger study. So broadly, FDA were okay with our approach there, including the doses that we to proposed to evaluate, and they gave us some useful guidance on some of the details around that protocol. So that was good. However, what they did say is that they want us to submit more juvenile animal data before we can start that study. Now you shouldn't think we haven't done juvenile animal study, we have. You have to test drugs in kids. And of course, that's what we're doing in all our other programs. So we've done one years ago. But the animals are not representative of human neonates. And so we really didn't want to do a study, an extra study ethically. We don't want to do it. And FDA has made a lot of comments about reducing animal testing, eliminating animal testing. So we were hopeful we wouldn't have to do that. But unfortunately, and again, we have no chance to discuss this. Unfortunately, they're saying we have to do that. So we will do it, and we are preparing for that right now. The other useful thing about the feedback -- sorry, encouraging thing about the feedback was that FDA asked us to have another meeting down the track to talk about the subsequent study, which will -- which we intend to be a Phase II [stroke 3] study. So i.e., a single study to seek registration. And so they encouraged us to come and talk to them about endpoints, the study population and safety monitoring. So that's good. Now obviously, when we come to that study, given what I've said earlier, I'll obviously be wanting to make sure that is a meeting that has the process that I described earlier. And then we switched to Pitt Hopkins. That's a different situation. So this time was a Type C meeting to discuss if we're going to do a study that has to demonstrate efficacy and safety in Pitt Hopkins, what are we going to use as the primary endpoints. That was really the main purpose of that meeting. And the result we got, again, without any ability to discuss it was effectively do the same thing as Phelan-McDermid Syndrome. So you can, if you want to use a PMS-specific CGI scale, if you accompany it with -- as a co-primary with an observer reported functional outcome measure. In PMS, our [PMSAC] endpoint is a PMS-specific CGI scale and the bit of the subdomain of the vineland that's the other endpoint is an observer-reported functional outcome measure. So that all seems clear and okay, except that Pitt Hopkins -- the problem with these observer-reported functional outcome measures, they were not designed for these syndromes. And so they're not as sensitive as the endpoints that we have designed, which are specific. Now in PMS, that's fine because we found one that really that was very sensitive in our Phase II trial, and we're very confident about. Pitt Hopkins, the kids are more severely impaired. Those measures become trickier to use in those kids. And that means if you get a smaller result on those endpoints, you need a bigger sample size to get your statistical power that you need. So if the outcome of just copying what we're doing in PMS is that we need hundreds of patients Pitt Hopkins syndrome, that's just not practical to execute that in this population. And our view is you shouldn't have to do that in a population that's rare. So what we are doing is looking at the alternative means of getting that sample size down. So different ways of analyzing the endpoint, possibly with things like responder analysis and other alternative trial designs that perhaps aren't just a straight comparison against placebo. So we haven't reached conclusions on that yet. We're still debating all of that. Then we will need to go back to FDA for further interaction. And again, we will make sure that it has -- we have a proper meeting, as I described earlier. Before we can then get into that study, which, again, we intend to be a Phase II [stroke 3] study that can provide evidence to support registration. So our target for both of these is to be able to initiate those studies before the end of the year. And given everything that's got to happen, it will be late in the year. Okay. So on to the third piece of news from last week. This is a pretty simple one. So the Rare Pediatric Disease Priority Review Voucher program was reauthorized by U.S. Congress out 30th of September 2029. And it's been reauthorized a few times. So there's every prospect that will get prolonged beyond then as well. God, this has had so many full starts in Congress with everything that's going on over there and often it was tied up with other legislation that kept getting stopped finally through, which is great news with such a good incentive for this sort of development. And for us, we have the designation that you need to qualify for a Priority Review Voucher across 3 indications, PMS, Pitt Hopkins, Angelman. PMS is the one, obviously, that we expect to get there first and get the PRV. You can only get 1 PRV per drug. So we can't get 3 here, we can only get 1, and we would expect to get it for Phelan-McDermid syndrome. You'll recall that Acadia got one for when DAYBUE was approved. And under our agreement with them, we got 1/3 of the value they realized for that. They sold it for USD 150 million. So we received USD 50 million. This time, of course, we'll own it 100% and a voucher sold recently for USD 200 million. Not clear yet whether that's a new market price or whether it will return to the USD 150 million, which have been sort of standard for a while, but whatever is an incredibly valuable asset that we will own as part of the Phelan-McDermid syndrome program. And I don't think that's factored into many valuations. So that brings me on to Phelan-McDermid syndrome. And out of all that news last week, for me, by far, the most important was the final bit of news on Friday that we first dosing in our PMS Phase III trial. I already made the comment as far as DAYBUE is concerned that by far, the most important thing is the U.S. market. And if we switch to 2591, again, by far the most important and valuable thing is the Phelan-McDermid syndrome program. So before I get into the detail, a quick recap on where we stand with this. We are trying to develop the first ever treatment for Phelan-McDermid syndrome here and we're leading the race to do that. We've got orphan drug rare pediatric disease, Fast Track designations from the FDA. We got great results in the Phase II trial. We've got clear alignment with FDA on a single Phase III trial design, including the endpoints. And then if we get a positive result from that trial, that will support the new drug application. So we go into this trial, our Koala trial in an extremely strong position. So the news on Friday was that the first patient had commenced dosing. And I just want to quickly recap on the schematic on the right-hand side of this slide. It's for what the trial entails. So there's a 4-week screening period. And then when participants successfully get to the end of that, they're randomized 1:1 to either drug or placebo for 3 months -- sorry, for 13 weeks of treatment. And then everyone, including the placebo patients can then continue treatment on the drug for 12 months. We are seeking to enroll approximately 160 patients, and that gives us full statistical power on each of those co-primary endpoints that I talked about earlier, and that's taking some pretty conservative assumptions about the outcome on those endpoints. So 160 is the magic number. So again, the specifics of what we announced last week. So on the left-hand side here, so first patient dosed, we also have more patients due to either start dosing or start that screening period in February and March. We currently have 2 active trial sites in the U.S., one on the East Coast, one on the West Coast and we have 25 families being referred to those 2 sites, including the ones that I just talked about. We have another 2 sites due to open this month in February and 20 others working through the process towards activation. We have 37 families who are on the wait list for one of those sites. So they -- that's where the 2 active sites are not geographically convenient for them. So they're waiting for those sites. Now it doesn't mean there are only 37 families interested in the study. So as each site activates, they will bring their own pool of patients. Those referrals are direct communication with us. Now you might ask, well, why aren't all the sites open on day 1? And so you need to understand there's an extremely painstaking bureaucratic process to open these sites, and it's got much more so in recent times in my experience. Some of these sites are big teaching hospitals that have a huge amount going on and bureaucratic, you got to go through contracting budgeting, resource allocation, training, et cetera. So it's a painstaking process, but it's going to happen progressively through the first half of this year. And then each site as they come on will then work through their group of patients. Something else we mentioned in the announcement last week that I want to bring up again because it is important. The Phelan-McDermid Syndrome Foundation having their biannual family conference in the U.S. in July. And as we were last time, we are again the presenting sponsor. So we are the main supporter of that event. Given the timing of it in July, it's a great opportunity to interact with so many families and increase awareness further about the study. So we think that's going to be really beneficial for us. And we're fully committed to supporting that community in any case, but I think it will be very valuable for us. So look, we're at the start of the journey, but really excited to have reached what is a big milestone and now to execute the rest of it. I have been asked before about what are the time lines for this. And so I'll repeat what I've said before. We're not giving formal guidance on that yet because we haven't got enough enrollment experience yet. We will do, I think, once we have. But I've pointed to the example of the Acadia Rett Phase III study, which was pretty similar in design, 180 patients and Acadia took 2 years from start to results for that study. And that implies 18 months to enroll the patients, 3 months for the last patient to do their 3 months of treatment and then 3 months to analyze and report the results. So could we do it quicker than that? I'd like to think there's a chance we could. COVID was around then. We need slightly less number of patients, 160 versus 180. But I think for now, that's a very objective benchmark for everyone, and we will do our utmost to try and come in faster than that. So I think that's it. I will -- sorry, it's not it. That's it on the news from last week, but sorry, I also said that I wanted to just quickly recap on case anyone is confused about this on the prioritization of indications for 2591. So also understand we're in an unusual situation here. Outside cancer drugs, it's very unusual to have a drug that could be applicable across so many indications. The indication we are prioritizing are really trying to give us the maximum commercial impact, and that really coincides with the maximum patient impact. So the 3 we're prioritizing, Phelan-McDermid syndrome, Pitt Hopkins and HIE, we believe we can have a leadership position in those indications. Phelan-McDermid and Pitt Hopkins, we are leading the way we think we can be first to market, do much as Acadia has done in Rett syndrome. HAE, we've got a drug that is quite different to any of the others being developed. We think, again, we can have a leadership position because of that difference. Now we have other indications, which are still in the picture, but they're just not the top priority. So we've got Angelman, Prader-Willi, SYNGAP1 and then Acadia has Rett and Fragile X. They're in different situations. Angelman, there's 2 Phase III trials running. One is going to read out this year. The data from that will be very instructive as to what we do next. Prader-Willi, there's a drug already on the market. There's another one in Phase III. Acadia obviously failed their Phase III trials. So again, we're watching what's happening there. SYNGAP1 is different. No one is in the clinic yet. So we do have an opportunity there, but it's a long way behind the others, and we need to work out what we're going to do there. And then, of course, Rett and Fragile X, they could have a very large commercial impact, much like the 3 that we are prioritizing. But they're in Acadia's hands, it's up to them. And also, of course, we don't own them 100%, we'll get a percentage of them rather than having 100% of them. So that's why the 3 that we're prioritizing are the priority. And then the final comment I'll make is again, just remember as well, the strategy here is to focus on orphan indications because then you can have uniform orphan drug-like pricing and you get the benefit of the exclusivity periods that the regulators give you on top of the patents that you hold. So that's, again, why we're focusing on orphan indications. So that is it. I'll finish there, try and get out of this stop sharing, right. Let's go to Q&A.

So we have submitted -- some questions submitted beforehand and some that are coming in during the webinar. I think I've answered quite a bit of this. I'm not going to repeat stuff that I've already said. Okay. I -- so there's one here. This is sort of slightly different to what I said about the Acadia and the European submissions. Was the unexpected negative year result of an inadequate submission, a lack of efficacy data or what? One point I'll make is, again, it's been approved in the U.S. It's been approved in Canada. It's been approved in Israel. So I don't think you can say it's an inadequate submission. Acadia hasn't made public the specific issues that the oral explanation was about. But again, I've talked about what I think needs to happen there, and I'm hopeful it can happen. Sorry, I'm just scanning through questions that I think I have answered all of those. There's one here. There's a bit of confusion here, and I've seen some commentary about this in other places. So its regarding the EMA's feedback to Acadia on inadequate dosage documentation. How confident are you that Acadia can provide the requested documentation? So there's some confusion happening here. There is a patent prosecution going on, on a patent in Europe with the European patent office around dosing in Rett syndrome. It's in the public domain. That has got nothing to do with the EMA process. It's completely separate. Patent office is completely separate. And it's nothing unusual with patents you go through this iterative process of debate on that. So it's got nothing to do with it. So that is a red herring. Sorry, just bear with me while I just check that I've answered all of this. Okay. So looking ahead 12 to 24 months, should investors expect updates on additional clinical programs or new formulation strategies for Neuren's platform, especially in pediatric or neurological indications? So look, I ended by going through our priorities at the moment and why there are priorities. We are always scanning for additional stuff, and that doesn't necessarily mean additional indications for 2591, but other opportunities. But for the moment, those top priorities are what I've just been through. Has any thought been given to using available funds to bring on additional resources to expedite other programs in parallel which is arguably as beneficial for the value of the company as the share buyback? So I guess that's saying, instead of the share buyback, could you put those funds somewhere else? So I want to make it crystal clear because I'm on the Board, I'm part of this determination. The buyback is not stopping us doing anything. The buyback is in addition to us doing what we want to do. So that's -- we're not stopping anything because of the buyback.

Jon, maybe while you scan some questions, I'll just jump in. There are a couple of questions that are tied to share price. One about how would we investigate further any irregularities in our share price? And also, is the share price the catalyst for the buyback? And would we have not done a buyback if the EU position was different and how aggressive will the buyback be? Perhaps I can try and wrap up a few comments all into one. Firstly, the share price movements over the last week, it is our intention to take it up to ask and to interact with the ASX about it. So that's something that we will do. In relation to is the share price the reason for a buyback, I mean, we're not going to pretend it's not a very, very important part of our deliberations. That would be silly. But we cannot do that, and we would not do that unless we were very confident in the prospects of the company, very confident in the cash that we have and the development activities coming and the forward projections of cash that we anticipate coming to the business. The extent -- I mean, how aggressive will we be, how active, et cetera, it's entirely at our discretion. And today, I wouldn't want to mandate exactly how that will look. We, as noted in our announcement, we will monitor everything, including other opportunities. If something is much more prospective that we should be doing, then we will do it. But we have the capability to do this. We think it's the right thing to do right now. And yes, we could wait. We could have a look at it every week until things look different. But our view is it's the right thing to do, and we're confidently progressing with it. So perhaps, Jon, I'll pass back to you for other questions.

Yes. Thanks for all of that, Patrick. Okay. So next one, what confidence can management provide investors that it has all the experience and skills required to successfully complete Phase III trials, especially in light of the recent feedback from the European regulators? So I think there's two separate things here. I don't think there's no connection with the feedback from the European regulators. As I said, that drug based on the data that was generated has been approved in the U.S. and Canada and Israel. And we've got a different situation here anyway. The endpoints used in that trial are quite different to the endpoints that we're using. So I don't think there's any connection there. But it's a fair question anyway. So let me answer that. We've grown from -- very deliberately from about 10 people to about 35 people. That growth has been almost exclusively in the U.S. and almost exclusively in clinical regulatory quality required to execute Phase III development. So we've certainly put a lot of thought into what we need to do that, and we think we have done that. When we get into the trials for HIE and Pitt Hopkins, we're likely to add more to what we've got currently. Next question, companies that fail to show healthy finances over multiple periods preclude conservative investors from considering them rather than buybacks isn't cash and focus on running the business better. Do you have a plan to improve the long-term business health? So again, I guess my basic answer would be that they're not mutually exclusive. Buyback isn't impacting any of that. I think as far as healthy finances, I don't think you can find a biotech company that's been in a better position than we have over the past 3 years and remain in. And for the long-term business health, that Phelan-McDermid syndrome program and the incredible value that, that can create if we're successful. That's all about the long-term business health as well as the continuing success of DAYBUE. So I just think the stuff in that question, the buyback really has absolutely 0 impact on it. Okay. So that is all the pre-submitted questions. Let me just go to the others, and I'll leave out the ones that you've answered, Patrick. So will DAYBUE STIX be able to be used by patients participating in the LOTUS real-world study of trofinetide in Rett syndrome. So the way LOTUS works is as new patients come in, the families can elect to be part of the real-world study. So of course, if people are going to start on the STIX, they can certainly be part of that real-world study. I don't believe there's anything stopping families if they want to switching from the liquid to STIX. And if they did that, I don't think there's anything -- any reason why they can't continue in the LOTUS study. So as far as I'm aware, I think that will be possible. And I think absolutely, I expect Acadia to be collecting data on STIX, including the GI side effects as to whether the profile is any different, which there isn't data on that so far, but I'm sure they'll be looking at that. Okay. Okay. That's a buyback one that I think you've answered, Patrick. Okay. So someone is asking for more information on the CHMP about specifics about what they were looking at and what data is going to be submitted. I'm not at liberty to say any of that unless Acadia does, I'm afraid. All I'll say is, as I said, I think they will put absolutely everything into that resubmission, and they're in a great place to know what they need to provide. Next question, is Neuren considering STIX for NNZ-2591? So I guess more sort of accurately, are we considering a powder formulation for 2591? Look, we're not at the moment because we don't think we need to. So remember, 2591 doesn't have the side effect profile that trofinetide has. The volume of liquid is much smaller. The liquid is different to the trofinetide liquid, and it doesn't require refrigeration. So many of the reasons for STIX are not there for 2591. Now could we consider that in the future? I mean it's quite possible if people wanted it, but it's not necessary now because of the characteristics of the drug. Okay. Again, that's a buyback question, which I think you've covered, Patrick, as is that one. There's a question here. I'm not going to read it because it's quite a sort of technical scientific question, but I'll try and give the flavor of it. It's really saying you're aware of a study around IGF-1 and its possible role in Alzheimer's disease. And I think the premise of the question is, can we consider exploring that. I said before that the problem with Alzheimer's and other massive neurodevelopmental disorders is okay, so they're not orphan. So you're not going to get orphan drug protection. So you must have water type patent protection. And we don't have that currently for these big indications, and it's not necessarily easy to get that. Secondly, and I think I've talked before about the price for something like that would be much lower than orphan. Now you might argue, well, the volume would be so massive, it wouldn't matter. But aside from that, the competition just about every company, everywhere is trying to develop drug for Alzheimer's. The studies are very long and very expensive. So we just think it's not the best investment for us in the time frame that we think our shareholders are looking for. So -- and we'll see where the science goes down the [track]. So a question again about STIX. What are the ingredients that are absent in STIX that could drive families to try it versus liquid? So yes, there is a much lower sugar content. There are preservatives in the liquid. There's a color. So there's a few things that -- and we don't think they have a big impact, but certainly, they matter to some families. Was the FDA encouragement on follow-on -- so when the FDA encourages us to have follow-on if meeting on HIE -- was that given knowing that our plan for the study was to be a registrational study or just a subsequent study? So the meeting was not about that study. It was about the IND and about the safety study that opens it. So we didn't really discuss anything other than our aspirations to then move into a study that would demonstrate efficacy. Yes. So we'll see where that goes when we have that subsequent meeting, but that's certainly our intention to do a Phase II/III study. Right. There's a question about timing of studies for HIE and Pitt Hopkins, which I think I said our target is to be able to initiate both by the end of the year. Is it likely in our view that HIE will run faster than PMS straight Pitt Hopkins syndrome? So that first safety study, which is a short study in a small number of people will obviously run faster than bigger studies in the others. But given that there's another study to come, no, I don't expect it will be faster certainly than the PMS program. So I'm not going to -- I'm going to answer this in sort of a little bit qualitative rather than quantitative. What has been the referral success rate to date, this is now talking about the Koala trial, i.e., anticipated conversion of referrals to become enrolled patients. I'm not going to give that detail other than say that there's -- there are always screen failures in every trial, and there will be screen failures in this trial. It's too early to know how many, but we don't expect that to be problematic given what we saw in Phase II. But yes, not every referral will result in a dosed patient, but we're comfortable with where we sit. And again, hugely encouraged by the excitement in the community. Next question, will having these sites open for PMS shorten the process of setting up sites if the Pitt Hopkins trial goes ahead? Again, I'll answer that more broadly. I think definitely, there are some synergies that I think would make starting up a Pitt Hopkins trial less onerous and shorter overall, and we may well have -- if we manage to have a smaller sample size and there may be less sites as well. If there are sites common to both studies, then yes, it may well help the opening process that you've been through that with PMS. Next question, do you expect to provide PMS trial enrollment updates over time? Yes, I do. We're not setting any definite pattern for that at this stage. But absolutely, we will provide updates over time. Right. In the early days of clinical trials for trofinetide, the dosage was structured that for 4 weeks, all patients received placebo and then those receiving the drug was switched over whilst the other stayed on placebo seem to better show the placebo versus drug performance. Why not this time? I actually -- I don't think that's right. Certainly, in my time at Neuren, we didn't do a so-called crossover study where people started on drug and switched to placebo. We didn't do that. I mean you sort of get that because they stopped treatment. So then you saw, well, what happened when they came off treatment, which I guess is the same thing. We didn't do formal crossover studies though in the past and not planning to this time. But even with the Phase II trials we've done this time, we've certainly see -- been able to see what happened to people when they stopped treatment and they regress. Should we think that 2-year benchmark is from this first patient dose date or from late last year when you started contracting and opening sites? So I think we -- the clinicaltrials.gov entry went up in November, which was the activation of the sites. So I think that's -- if you're looking for the equivalent to what Acadia announced, that would be that. It would be in November last year. Okay. Is HIE designated as an orphan drug in the HIE program? Not yet, but we expect that other people have got orphan drug designation in the past for HIE. So we expect to get it. We haven't got it yet, but we'll go through that process. Would you please refresh us on the side effects of NNZ-2591?Is diarrhea a big issue? So I mean this is, I think, well publicized that certainly in the clinical trials that were run, diarrhea was a prominent side effect. It wasn't apparent in everyone, and it wasn't severe. It was mild to moderate diarrhea, but it was very common. I think in the real world, once it got launched, that was seen, not surprisingly. And then what's happened since is that two approaches to try and manage that one to titrate up the dose rather than going straight into the top dose, which is a big load on the GI system, start lower and get the body used to it. And secondly, a lot of different dietary things that families have tried. And sometimes it's not the same thing for every child. So there's a lot of stuff that's been learned and there's work to reduce the impact of that. And you can see that in the latest real-world evidence data that Acadia has published that it's definitely now much less of an issue than it was back in the clinical trial. But it's still there, but -- and that's part of when you're trying to get new patients on to the drug, you've got to make the patients and the doctors understand that this is -- you can deal with this, and this is how you do it. Any update on the reimbursement process in Canada? So no, I don't have an update on that. And I think hopefully, you're aware, Acadia went through an appeal process in that. In that case, it wasn't different people looking at it. It was the same people, and they came to the same conclusion. I know the Rett community in Canada galvanized themselves and is lobbying hard, but I don't have any update on any further on that at this stage. Again, I'm really hopeful that the Rett community in Canada is going to get this. I mean it's not a good situation. Any thoughts on potential EU pricing? Yes, I can't really comment on that. I mean it's completely in Acadia's ballpark. I think we need to get approval first. When you get approval, you can launch in Germany and have six months of re-pricing --pricing at the price that you set and then negotiate the long-term price. So it's going to be quite a long time before we know what a long-term price looks like in Europe. Obviously, every incentive for Acadia to maximize that when they come to that point. Okay. Another question about my 2-year benchmark from the Acadia study. For clarity, is the PMS Phase III T horizon started last Friday, I think I've dealt with that November would be the start. And the endpoint is FDA acceptance of the Phase III results. No, I'm talking about announcement of the results by Neuren, which would be the equivalent of Acadia announcing the Rett Phase III results. And that's the thing that's going to cause an enormous creation of value for Neuren if they're positive. Okay. Next question, why -- sorry, I'm just watching the time here. I'm going to try and wrap this up very soon. We've got just a very few questions left. Why was a share buyback preferred over paying a dividend? So I think we'll -- we carefully consider this as a Board, and we do all the time. We think in this particular circumstance and the reason we've activated the buyback after what happened last week, we think a buyback is a sensible way to go. But we're certainly keeping the idea of dividends in the conversation for the future. Patrick, anything else you want to add to that?

No, Jon, I agree completely.

Okay. Has Neuren received any recent M&A or partnering interest? And I won't surprise you to say I'm not going to comment at all about any specifics. I think we've said before, Gerry and I went to the Jefferies Conference in London in November and met with many companies, and we continue to have dialogue with lots of companies. Would a successful future HIE trial open the door for use of 2591 as a treatment for general brain injury? So my comments about orphan indications apply here. So if there were orphan indications or subsets of general brain injury, that could be possible. Of course, we've got a bit of a history in brain injury, and we want to be absolutely sure that we can have a successful outcome. But certainly, it's not out of the question. I realize it's Acadia's call, but is it fair to say that Fragile X development has been canned or any developments you can say? So you're right, completely up to Acadia. I don't think you can say it's been canned because if you look at Acadia's pipeline slide, it's on there. I think Catherine even included it in her recent comments that she made. So I still think it's a possibility. We still think you could have a great outcome there. But yes, it's up to Acadia. Interesting one. Can you tell us a while -- sorry, can you say a little more about the ASX aware letter following Acadia's projection about DAYBUE sales in 2028 which started the share price slump? So look, I think -- I feel like the timing of that was sort of coincidental because I think for me, becoming public that Acadia had an oral explanation at EMA for me was sort of the start of share price came down. But it just so happens this coincide with that. The ASX Aware letter obviously is in the public domain, and there were two things they asked about. One was the ability to make that projection. Of course, it's Acadia's projection, not ours, but I guess by publishing it, it makes it our projection. Did we have the right basis to make that? And we answered that fully in the response in the ASX aware letter. And then they asked about when we received the usual continuous disclosure, question about when we received the information. So to me, there was nothing to it at all. I was disappointed that, that had to be put out in the public domain because I really thought there was nothing in it at all. And again, it's not news that we've gotten are holding on to and nothing like that. It's stuff that's been made public by Acadia that we felt shareholders ought to be aware of. So I was pretty disappointed that, that was all out in the public domain, but it is what it is, no big deal, and I don't think it has anything to do with the share price. Right. That's not a question. It's a comment. Thank you for that comment. Okay. So I think we're at the end of the Q&A unless Gerry or Patrick, you can see that I've missed anything.

No, you've covered it all, Jon.

Great. And I think we're well -- probably well over time anyway. So I don't know how you -- how many of you are still with us, but if you are, I really appreciate the time that you've given to listen to us today. Huge week last week, big steps forward in many respects, big overreaction to, I think, the first of four news items. We think we're in a great position, buybacks in place in response to that, and we can't wait for the rest of the year to unfold. So thank you all. See you soon.

Thanks, everyone.

Thank you.