Good morning, everybody. Thanks, Jim. If we could just close the door. Good morning, everyone. My name is Patrick Davies, and I'm the Non-Executive Chair of Neuren Pharmaceuticals. It's my pleasure to welcome you to Neuren's annual shareholders meeting. I note there is a quorum present, and I therefore declare the meeting open. Before we proceed with the meeting, I have a couple of quick housekeeping points. I'd appreciate it if you could turn your mobile phones to silent. Recording devices and cameras must not be used during the meeting. In the event of an emergency, please follow the emergency exit signs and instructions of the venue staff. We're pleased to facilitate a hybrid meeting through MUFG Corporate Markets online platform, enabling shareholders to participate in the meeting irrespective of where they are in the world. I welcome those of you participating online.
The agenda for the meeting is as follows. Firstly, I'll present my address. Following that, Jon Pilcher, our CEO and managing director, will present his review of Neuren's activities. We'll then proceed to the formal business of the meeting, which includes the resolutions. Following the conclusion of the meeting, I invite those shareholders here in person to join me, my fellow directors, and senior management for light refreshments. In the room with me today are my fellow non-executive directors, Jenny Harry, Dianne Angus, Joe Bassil, and I think all of you would know our CEO and managing director, Jon Pilcher. At the back of the room, doing all of the hard work, as always, is our CFO and company secretary, Lauren Fraser.
2024 was another highly successful year for the Neuren business, with record financial performance, record sales of DAYBUE, and two more successful phase two trial results for NNZ-2591. For the second year in succession, Neuren received the Australian Growth Company of the Year award for health and life sciences. Across 2023 and 2024, our income from for DAYBUE was $445 million at a 100% pre-tax margin, which led to cash of $341 million at 31 March 2025. That cash has come from income, not capital raising. This puts us in an excellent position to pursue the realization of the value of NNZ-2591, which has the potential to be many multiples of DAYBUE. Relative to our peers, we believe this provides a unique proposition for investors, a valuation backstop, as well as the potential to add much more value using existing funds.
It was only a few years ago that we had to work really hard to raise fresh capital of $20 million to support our growth plans. Earlier this month, we reported that our royalty income from ACADIA for the first quarter of 2025 alone was $13.5 million, which underlines just how much our financial position has strengthened on the back of the long-term partnership we put in place with ACADIA for trofinetide. The $50 million share buyback program we commenced in November last year, which remains ongoing today, is a further statement of our confidence in the current and future cash flows of Neuren. Despite this huge progress and all nine analysts that cover Neuren with buy recommendations at an average target share price of $26, our share price has fallen significantly from its peak, which is frustrating and disappointing.
Neuren was the best-performing ASX 200 stock in 2023, a year in which DAYBUE was approved and launched together with a first positive phase 2 trial result for NNZ-2591. In 2024, we were impacted negatively by momentum trading, initially triggered by a switch to negative sentiment about DAYBUE sales, which has ultimately proven to be inaccurate. In the early launch period, with limited experience, there was heavy focus in the investment community on quarterly sales rather than the long-term opportunity for Neuren. In addition to this, whilst there is much media and industry attention on the actions of the new administration in the United States, we currently see no impact of this at all in our business. However, we are in a challenging and volatile market environment with uncertainty negatively impacting investor sentiment and risk appetite for the biotech sector broadly.
We continue to maintain that the DAYBUE launch has been very successful and better than comparatives, with net sales reaching 348 million in the first full year of sales. ACADIA has committed substantial additional resources to expand DAYBUE in the U.S.A and has forecast continued growth in 2025. The recent reporting for Q1 2025 highlighted renewed growth in the number of active patients to a record 954. 65% of patients currently on therapy have now been treated for more than 12 months. This provides a very stable base, which means that sales have become much more predictable. There are still two-thirds of the expanding pool of diagnosed patients in the U.S. who have not yet tried treatment. This, together with the coming expansion into Canada, Europe, Japan, and potentially other countries, provides substantial upside and a long-term growth opportunity for Neuren.
ACADIA has done an impressive job so far, and with new commercial leadership and initiatives in place, is now in an even better position to maximize that global opportunity. Most importantly, the stories from families of benefits that children and adults with Rett syndrome are experiencing on DAYBUE are heartening and extremely motivating for the Neuren team. We are very pleased that ACADIA has announced the appointment of a distributor to facilitate named patient supply outside North America, Europe, and Japan, especially as this may potentially include the Pacific region. For NNZ-2591, we were thrilled that during 2024, the positive phase two trial results for Pitt-Hopkins syndrome and Angelman syndrome were consistent with the Phelan-McDermid syndrome results, validating our thesis that NNZ-2591 can potentially have a broad impact on neurodevelopmental conditions.
We were very pleased with the outcome of our end of phase two meeting with the FDA for Phelan-McDermid syndrome, enabling us to move straight to phase three with a similar program to the successful DAYBUE program in Rett syndrome. Last month, we were delighted to announce that we had reached alignment with the FDA on the efficacy endpoints, which is the most complex issue when you are leading the way as the first treatment, and there is no precedent to follow. We went through a similar journey with the FDA to align on efficacy endpoints for Rett syndrome. Overall, we believe that the success of DAYBUE de-risks the NNZ-2591 programs, given the similarities in clinical profile, scientific rationale, trial design, and endpoints.
Building on the Rett syndrome experience, we are eager to embark on the first-ever phase three trial in Phelan-McDermid syndrome, aiming to provide a first treatment option to that community. We are excited to also now be targeting HIE, a devastating type of brain injury in newborns. We believe that NNZ-2591 can potentially provide a highly differentiated form of treatment, continuing beyond acute treatment in the neonatal intensive care unit to target both the acute effects and long-term neurodevelopmental impairments resulting from HIE. During the past year, we have been transitioning Neuren's capabilities from phase two development to phase three development. That has required some changes in the skills and location of roles, as well as a major focus on uplifting the sophistication of Neuren's quality systems.
We are delighted to welcome new team members to our company, and on behalf of the board, I'd like to thank the whole Neuren team for their diligence throughout this transition and for all their many achievements during the year. Last week, we announced the approval of some new share options with vesting conditions that incentivize the Neuren team to achieve the important milestones for NNZ-2591 that will deliver value over the next three years and align their interest in the outcome with shareholders. 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. With DAYBUE generating substantial sales in the United States and with ACADIA pursuing further geographic expansion over the near term, we will continue to receive large ongoing royalties and future milestone payments.
We now have a path forward to move NNZ-2591 into a pivotal trial for Phelan-McDermid syndrome later this year, and we are pushing ahead with our development plans for other indications. We have the financial resources to confidently execute our plans, and we remain bullish about the shareholder value creation that Neuren can deliver. I'm not alone in holding this view. As mentioned earlier, all nine analysts that cover our company have published detailed independent analysis of the upside they see in Neuren. We are grateful to all our supportive shareholders and can assure you that we will continue to evaluate all options to maximize shareholder value. Last but not least, we thank the patient communities across the indications we are pursuing for their support, determination, and courage, which is so critical to achieving the outcomes we are all striving for.
I'd now invite Jon to take the stage and make his presentation. Thank you.
Thank you, Patrick. I thought that was an excellent summary of where we've got to as a business. A lot of what I'm going to say is actually going to be repeating the stuff that Patrick's told you, but I'll go into some more detail on some aspects, obviously. Before I do, though, I want to say huge thanks to Lauren, our CFO and company secretary. There's a massive amount of work that goes into today, but not just today, all the other annual reporting stuff that precedes it. Thank you, Lauren. Also, thanks to the team from our share registry, MUFG, for all their work today as well.
As always, before I carry on, I just have to remind you that in my comments and in the slides are forward-looking statements subject to risks that could lead to different outcomes. I think if this is a little bit of a review of the past, then it would be remiss of me not to start with the incredible financial outcome that we've had. It's not just in 2024, it's 2023 as well. If you look at the total income for shareholders, so post-tax profit and foreign exchange gains, $166 million in 2024, and that was off the back of $157 million in 2023 from zero the year before. An incredible transformation there and just shows the power of the fact that the revenue we get, as Patrick said, is 100% pre-tax margin. Straight to the bottom line. A few other elements of this.
Our corporate and admin costs 5 million for the year. We continue to run the organization extremely leanly. That was actually more than covered by our interest income for the year. All of this allowed us to invest $33 million in the development of NNZ-2591 and still produce that financial outcome. As Patrick mentioned, more than 350 million of cash. If you think about the past as to what we've achieved, we've made huge strides forward, whether you measure it as what happened in 2024 or what happened since the last AGM, which would be the second half of the left-hand side of this slide and the first half of the right-hand side. By any measure, we've achieved a huge amount. I'm not going to go through everyone individually, but just pick a few highlights out.
The sales outcome on debut, which I'll cover in more detail in a minute, approval in Canada, filing the application in Europe, and then starting named patient programs in other territories. Huge progress there. All those positive phase two results Patrick referred to, three different positive phase two results, and then that alignment across two meetings with the FDA to go forward into phase three. Really, a huge amount has been achieved over that period, as I say, whichever period you choose to measure it. To be honest, the best is yet to come. We're very proud of what we've done so far, but really the next stuff, which is the stuff that isn't ticked on this slide yet, is really important, and we're all highly motivated to achieve that. I'll come back to that at the end of the presentation.
Having said all that, let me just step back and let's just remind ourselves the endeavor that we're all on here, both ourselves as a company and you as shareholders. Our two drugs, trofinetide and NNZ-2591, improved copies of naturally occurring peptides that play an important role in the brain and in the biology of IGF-1 in the brain. This critical growth factor helps the formation of new connections between the brain cells, the maintenance of them, and the repair of them. In the brain, neurons have millions of branch-like connections through which signaling travels, and that governs everything in your body. In everything we're trying to treat here, it's not correct. It's not working properly. That's the power of this, that that outcome can come from many different things.
All the syndromes that we're trying to treat, they're all caused by completely different genetic mutations, and yet they all have this same feature downstream of those mutations. That's the power for us that we don't have to have multiple drugs trying to treat the root cause. We can have a single drug trying to treat the same thing across multiple syndromes. As you know, because you've got this common feature, the clinical outcomes across all of these things, again, despite the fact that they're from very different origins, are very similar. Sadly, it's a terrible range of problems that affect just about every aspect of life. Highly debilitating, huge impact on the patients and their families for life. At the moment, as our drug is approved for Rett syndrome, there is another drug that's just got approved to treat Prader-Willi syndrome.
Other than that, there are no treatments for any of these things. So there's massive unmet need, and we're all highly motivated to do something about that. The patient journeys in this are everything, as Patrick said at the end of his address, and I really recommend if you haven't already done it, there's a blog that you can freely access on the web, Trail to a Texas Trial, which tells the story of an incredible mom, Melinda, and her daughter, Caitlin, and their journey in Rett syndrome and on DAYBUE specifically. It's incredibly motivating if you read any of that. In Phelan-McDermid syndrome, at our first FDA meeting, we showed a video of a child, a boy who'd been in our clinical trial, and both him and his parents. Again, challenge you to watch that without crying. Unfortunately, I can't show it publicly today, but very powerful stuff.
Again, that's why we're all doing what we're doing here. The right-hand side of this slide is new, as Patrick mentioned, HIE, and I'm going to talk more about that in a minute in more detail. Again, very interesting that it's not a genetic mutation. That's an injury, completely different origins. Again, the clinical outcome is quite similar, very similar to the neurodevelopmental disorder outcome. We think we can have a big impact here and be a new form of treatment. We have a long heritage in brain injury, which I'll, again, I'll come on to in a minute. Last thing I wanted to say before we leave this slide is just remember, again, from a business point of view, all of these conditions are orphan drug indications, and our whole business is orphan drugs, which means a number of things.
Really importantly, very limited competition. If you're going to try and develop drugs for mass market indications, you're going to be competing with 100 companies easily. Here, we really have a small handful of competitors. Secondly, you get much better pricing outcomes. Even though the numbers of patients are relatively small, although in our case, it's still thousands of patients, because of the pricing, you can get hundreds of millions of dollars of sales across each of these indications. From a regulatory point of view, you get a much more favorable run-through with the regulators. It's much more a negotiation of how much evidence you need to supply to get approval. It's not everything by the book, which again is a huge advantage. Once you get to market, you get protection against generics.
Generic companies are out there scouring patents that they can challenge so that they can get in and copy drugs. With orphan drugs, for pediatric purposes, seven and a half years in the U.S., 12 years in Europe, 10 years in Japan, the regulators will not approve a generic whether or not you have any patents. There is no point in them challenging patents. You should not underestimate how important that is. That is ultimate protection for your commercial outcome. We think orphan drugs is a fantastic space to operate in, particularly for a small company. That is why we are doing that, in case anyone wonders. That is the sort of the theory behind what we are doing. Now let's talk about, I guess, the prospect for investors, the proposition for investors.
I think, and of course I would say this, but I strongly believe you've got the best of both worlds with Neuren. Not only have you got the $341 million of cash that Patrick referred to, which has not come from capital raising, it has come from income, but you've also got the ongoing income that is coming to us, 100% pre-tax margin from ACADIA for DAYBUE as it expands around the world. That cash has come from that. The bottom two bars in this are really the same thing, giving you an incredible foundation. Even if, as a company, we just had that, that would be a great outcome. We have not just got that. We have this huge potential value uplift from NNZ-2591 because it is applicable across multiple indications, which increases the numbers of everything multiple times.
Also because we have now got the capability both financially and skill-wise to take it much further than we were able to do with trofinetide. The further you take these things along the development path, the more their value increases. If you can take them to the end, there is an exponential increase in value. I think that is a fantastic proposition for shareholders. Often, if you are chasing that big value uplift, what happens is you have 100% downside. You might have this great upside, but if it does not work, you have 100% downside. You might face multiple capital raisings along the way to get there. Again, with Neuren, you do not have either of those things. Your downside is protected by that DAYBUE value, and we do not need to raise capital.
Again, keep saying this, you've really got the best of both worlds, I feel, with Neuren. I'm now going to just touch on the two different aspects of the business, DAYBUE and NNZ-2591. Obviously, underpinning everything with DAYBUE is the economics we get from ACADIA, which are very strong. They're split between North America on the left-hand side of the slide and outside North America on the right-hand side. The ticks are the payments we've already received. In 2023, $140 million came to us, and in 2024, 100 million. That was just from milestone payments. Of course, you've got the royalties on top of that, and those are growing strongly, as we'll see in a minute. This is such a strong financial foundation for us and is only going to grow as time goes on.
Now let's just talk about DAYBUE in more detail and start with the sales in the U.S. Of course, ACADIA had their Q1 earnings call recently, and I'll come back to that in a minute. The outcome in 2024 was $348 million of sales, U.S. dollars of sales in the U.S., which was 97% up on the previous year. They've guided to further growth to between $380 million and $405 million in the current year. On the right-hand side, you see the royalty outcome that that gives. Our royalties are $27 million in 2023, grew to $56 million in 2024, will grow further to between $62 million and $67 million in 2025. This is a great outcome. The royalties coupled with those extra milestone payments has obviously had a massive impact on us. Let's drill down more into the DAYBUE sales.
This time, the chart is showing the quarterly sales since launch of DAYBUE. You can see a few things here. In fact, there's something missing on this slide. I don't know whether it's on the one that's lodged. Hopefully, they're there. They're little comparisons to another drug, SKYCLARYS. I'm going to mention it anyway, even though I can't see it on this slide. A drug for Biogen, a much bigger company than ACADIA, that launched about the same time as DAYBUE and for a very similar size population, similar sort of pricing point, seen as a leading drug for Biogen. They paid the company they bought it from at the point when it had been approved in the U.S. and was filed for approval in Europe. They paid $7 billion for that drug.
DAYBUE has outperformed it every single quarter, and the gap was quite big in that last quarter. It is a fantastic outcome. Of course, what happens in the early days of a drug launch like this, there is no history. No one really knows what is going on, and it is quite volatile. We are certainly, from a share price point of view, impacted by that. If you look at this chart, you can see that there is a pattern of the Q1 being less than Q4 in the previous year, which has now repeated for two years. There are seasonal factors here where families will get refills that were due in January. They will get them in December instead to see them through the holiday season. That causes sales to move from January into December, which causes the Q1 to be lower than the Q4.
Now, with the first time that happened last year, no one was expecting that. I think it even caught ACADIA a little bit by surprise. When they announced that reduction and they then reduced their guidance for the year's sales because of that, we got absolutely clobbered from a share price point of view. Again, as Patrick mentioned, too many people really fixating on that quarterly sales because there was no experience. Whereas now, a year on, it is now very predictable what is happening. The rest of this year, we expect growth each quarter like you got last year. It steps down first quarter, but then the whole thing is higher than the previous year to get to ACADIA's guidance.
It is predictable now because 65% of the patients have now been on treatment for more than a year, which again, there was nothing like that, obviously, a year ago. It is much more predictable now what sales are going to do in the future. A big event happened in ACADIA towards the end of last year. A new CEO who also brought in a new head of commercial. They both have huge experience in commercializing drugs both in the U.S. and outside the U.S., they instigated some changes. A 30% increase in the sales force for DAYBUE and also really uplifting the sophistication of the marketing, getting information out to the community.
That is physician to physician, physician to patient, family, I should say family rather than patient, and then family to family, getting information out about the positive impacts that people are seeing with DAYBUE and also that the common side effects can be managed effectively. Now, all of these initiatives, they do not expect to have an impact really until the second half of this year. We think the new leadership there are really giving this the best possible chance to get a great outcome. I think that the potential here is enormous because there are still two-thirds of the known Rett patients who have not tried treatment yet. Not only is the pool of diagnosed Rett patients growing, it has grown from 4,500 at launch to 5,800 now as awareness builds, but also you have two-thirds of the patients still yet to try treatment.
A lot of those patients are seen sort of around the country in the U.S., so not in the centers of excellence for Rett syndrome, which is where a lot of the initial sales came from. ACADIA's got to access this much broader population of patients, and that's what all of these initiatives are aimed at doing. You can see if you think about only one-third have tried treatment, simplistically, if two-thirds try treatment, it's going to double our royalties and also move us to the thresholds where you get more milestone payments. There really is huge opportunity here just in the U.S. That's not the end of the story. Again, this slide has lost the world map, but I'll talk to it anyway. Look, this has always been a global opportunity for us.
You'll remember we did an expanded deal with ACADIA on extremely favorable terms to expand their rights to the world. They're now making great strides towards bringing DAYBUE to patients around the world. Already got approval in Canada, as I mentioned earlier, filed for approval in Europe, expecting approval in the first quarter of next year. In Japan, they're about to start a small clinical trial. It's not like the phase three trial for the US. It's a small trial in a Japanese population, which you have to do to be able to file for approval in Japan. You've got this cascade of growth in the US, Canada, Europe, Japan, and then other territories come on. As Patrick mentioned in his address, we're really pleased that ACADIA's appointed a distributor to look at name patient supply in other areas around the world.
I very much hope it's going to include Australia and New Zealand. Again, that's going to be all extra sales coming in from around the world. The other thing they're doing in advance of approval in Europe, again, having sort of early access programs, and they've just started that in Germany. The importance of that is not so much the revenue it brings, although it will be revenue. It's getting the product out into the hands of physicians and families in Europe so they have experience of the drug and the positive impacts you can see and managing the side effects before you get to the full commercial launch next year. That's really important what they're doing there. That's all I'm going to say on DAYBUE. I'm sure we'll have some questions later. Let's move to NNZ-2591.
A multiple indication story, as I've said. I guess simplistically, you can think of this. We're trying to build the pie as large as possible, but with an indication leading the charge, which is Phelan-McDermid syndrome. Incredibly happy to have agreed with the FDA what's going to come next, and I'll talk about that in a second. We're moving Pitt-Hopkins and Angelman along behind that. HIE now comes into the picture. At the moment, there's no ticks on this slide, but we think we can fill those boxes rapidly with HIE. I think it's a really interesting opportunity, which I'll come back to in a second. There are other indications pending. It's Prader-Willi, of course.
We have to make a commercial judgment there because a product's just got approved, and ACADIA's in late stage of a phase 3 trial with another product. We have to make a commercial competitive judgment there. We've got other indications we're working on, I think, as you know, which we will talk about in due course. Again, just trying to build the pie as large as we can, but it's got to be a credible pie. We have to have a way forward with the FDA, which is what we're working very hard to do. Just a quick recap on why do we think this multiple indication strategy works. I've already talked about the scientific basis for it when I talked about that slide earlier.
We have hard evidence from three phase two trials across three different indications where somewhere between 67% and 89% of patients showed improvement with 13 weeks of treatment. The type of things that improved were very consistent across the trials: communication, behavior, better cognition, and social interaction and motor improvements. They are the really important things in these indications, and it was very consistent across all of them and consistent within the trials themselves as well. Consistency of data is really important. There is no point in a trial result where one thing looks brilliant and the rest confounds it. FDA do not like that. The more consistency you can have in your data, the better. You could not get more consistent results than these. After these results, we were sure that our thesis is right.
Now, probably the most exciting thing for us in this whole presentation really is we're close to being able to commence the first ever phase three trial there's ever been in Phelan-McDermid syndrome. We feel really good about this for two reasons. It's very similar to the phase two trial we run, but it's also very similar to the phase three trial that ACADIA ran with Rett syndrome, which, of course, was successful. The similarities of the drug as well, as Patrick again mentioned in his address, mean we really think the risk of this is driven lower and lower by those three things. No trials are risk-free, but we really think this has got as good a proposition for success as you could have. Let me just quickly run through what it's going to look like.
Today, we're saying for the first time it's 160 patients is the size of the trial. They'll be randomized one-to-one as they were for Rett syndrome, 80 on drug, 80 on placebo. The people on drug are going to get the same dose as we had in phase two. It's the same age range as we studied in phase two. It will be followed by an open label extension, as was the Rett program, to follow everyone on drug out to 12 months, which gives you a rich amount of information that the primary reason for it from an FDA point of view is safety to make sure that the drug's safe for long-term use. You actually get a rich source of information about longer-term efficacy outcomes and the maintenance of effect and the people switching from placebo to drug, what happens to them.
That's an important part of the program. The expected total cost of the program, between $80 million and $90 million, which is within that range that I always talked about of $50 million-$100 million. We're comfortably going to fund that from our existing cash. No additional funds required. We feel really good about this design. Let me just talk specifically about the endpoints because I think, as you know, we had to have a second meeting with the FDA to agree these efficacy endpoints, which, as Patrick said, is the most difficult thing in these indications. If you can get there, then you're in a position that no one else is in. We're really pleased with the outcome. It's two co-primary efficacy endpoints. Both have to hit for the trial to be positive.
That's exactly what we had with Rett syndrome. And again, similarly, one is a clinician measure, one is a caregiver measure. So you're getting two different viewpoints of the outcome. Both of these had a really strong result in our phase two trial. So the first one, which is the physician measure, the PMSAC was called the CGII in the phase two trial. 16 out of 18 patients showed improvement on that measure. And the mean score of 2.4, three and below is improvement. And to give you a comparison, the Rett phase three trial, the drug group, 3.5 was the mean. We got 2.4 in the phase two trial here. So really strong result. And then the other aspect, which was the thing that, again, we agreed with FDA, was to look at one specific aspect of Phelan-McDermid syndrome, which is receptive communication.
Using a measure that they're very familiar with, the Vineland, which has been used for a long time in many different settings. I'll come back to why receptive communication is important in a minute. Again, the really strong phase two results. Sixteen out of eighteen patients again showed improvement on that measurement. The mean improvement was 7.5, and the mean baseline was 29. That means you've got about a 25% improvement on average, which is, again, a really strong result in only 13 weeks of treatment. Why receptive communication? Really important skill for these kids. If they can't receive and interpret and act on information, that makes a lot of other stuff very difficult. It's a foundational skill. I think that's why we think it's a great thing to be measuring in this trial. That's what we're about to embark on.
Team can't wait. It's been a huge amount of work to get to this point, but we're highly motivated to now do it and get to the outcome as we're seeing in Rett syndrome. Before I leave Phelan-McDermid syndrome, I've just brought this up again from our phase two trial result. I'm not going to go through all of these, but all these testimonials from both clinicians and caregivers, and I mentioned the video we showed FDA earlier on, such great things being seen. I'll just focus on a couple of things. From the clinicians, able to focus work at school, both of the things they always enjoy, and to new tasks. Teachers noted improvement in learning new skills. You see similar sort of comments from the caregivers. Again, that's really important. Again, I think receptive communication ties into that, as I said.
One thing we're hoping we can get these kids from phase two back onto drug in the open label part of the phase three trial. It would be fantastic to get these kids back on drug given what happened in the phase two trial. That's Phelan-McDermid syndrome. Now I want to talk about HIE just for a minute. As I said, we're really excited about this. Probably, I think it came a little bit out of left field for people, but actually, Neuren's got a long history in brain injury. Both our drugs came out of Auckland University all those years ago, and were both initially earmarked as treatments for brain injury. In fact, Sir Peter Gluckman, who's a famous scientist in New Zealand, was the advisor to the Prime Minister for some time. He was Neuren's first chief scientific officer way back in Auckland.
He did a lot of the foundational work on IGF-1 in brain injury. And coincidentally, in HIE, he was a big figure behind the trials of therapeutic hypothermia, which is the standard of care for HIE. He is a big figure in getting that approved. Again, there is quite a nice virtuous story here. We are going back to our roots to do this. Look, HIE, for me, it is the same but different. It has all the advantages of everything else we are doing. It is an orphan drug. It is paediatric. There is huge unmet need, no products approved, very little competition in development. It leverages everything that we have done with 2591. All the non-clinical, the manufacturing stuff, it leverages all of that. It is different. A few ways that it is different.
The patients, you have not got a pool of patients out there that you have to identify through genetic testing and find them. You have patients, sadly, coming every year. Every year, there are new cases of HIE, and they are all in ICU units in hospitals. You know where they are. You know how to get to them. That bit is actually much more favorable than the other things we are working in. We want to explore the possibility here to do a phase two-three trial. We are not planning to do what we have done with the other indications and to do a small little clinical proof of concept and then try and move on to a registration trial. We want to find a way where we can seamlessly move to registration with this.
Now, that is totally dependent on a conversation with FDA that we intend to have later in the year. That is certainly what we would like to do. When you're running a trial, again, the fact that these kids are in the ICU units in hospitals, many of them large hospitals in cities in the U.S., running a clinical trial, you can potentially do it with fewer sites too. It is very attractive from that point of view. We think there's great scientific basis for what we're doing, as I said, all the way back to Auckland days. We have a range of data from lots of different models, both in vitro and in vivo. Some of it comes back from the Auckland days, and some of it is stuff we've done more recently. We think there's a real strong scientific rationale.
I mentioned therapeutic hypothermia. This is what they do with these kids, a standard of care. They cool them, either just the head or body for a few days to try and limit the impact of the injury. I did not mention this, but this comes from the injury coming from usually interruption of blood flow. Not enough oxygen has got to the brain, and it has the same impact as an injury. The therapeutic hypothermia is trying to cool everything down to dampen that impact. It does improve survival because, sadly, these kids, some of them will die. That has improved survival. As for whether it has improved the long-term impact, it is less certain. We think we have got a drug that that is exactly what it is going to do, is to improve that long-term impact.
Everyone else who's trying to treat HIE is usually focusing on that initial injury period and trying to do what hypothermia is doing, trying to improve that initial injury. With our drug, we want to treat for longer and have a longer-term impact into the future. As I mentioned, as with the others, eligible for orphan and also the rare pediatric disease designation, which gives you eligibility for the priority review voucher provided that program gets reauthorized. We're really excited about this. As I said, that conversation with FDA, as always, is really important, which we're preparing for. Sort of the market opportunity here, there's a lot of numbers in this slide, but you get to an addressable market of about, we think, about 6,000 newborns in the U.S., 7,500 in Europe, about 1,000 in Japan, and about 19,000 in China.
These numbers are very similar to the Rett syndrome numbers. Really, they're very similar. Of course, as I said, there's new patients every year. These patients are reoccurring every year, sadly, whereas the Rett patients, you've got a static pool that you're trying to get to. Again, we think this is really attractive from that point of view. The last thing I'll say on HIE is, as with all our indications, we only get anywhere because of the partnership we have with the community for these things. HIE is no different. Hope for HIE is the advocacy organization that we're already working with. That's their website on the right-hand side there. The KOL that we're principally working with, Brian Kallisch, incredibly impressive person, as they all are.
These people are so impressive, and they dedicate their lives to trying to do something for these kids, and in this case, newborns. I'm going to read what he said about our program because it's pretty powerful, I think. Brian said, "I'm genuinely excited about Neuren's development program for NNZ-2591 in HIE. There's a tremendous need for therapeutics to address both the acute and chronic consequences. NNZ-2591 has demonstrated an ability to target early effects of brain injury as well as longer-term effects on brain development and neuroplasticity. Its role in restoring IGF-1 levels in the brain, which are significantly impacted by HIE, is very promising. I'm looking forward to working with Neuren to make this program successful." We are obviously very much looking forward to working with Brian. He's at one of the big hospitals in Boston.
There are a few big hospitals in Boston, which, again, there's access to a lot of patients just in Boston. Watch this space on HIE. Obviously, we'll update further on the development plan and particularly when we've spoken with the FDA. I said I'd come back to this milestone slide, and I will here. I'm not going to talk about what's been achieved because I've already done that, but just focus on those last things. The rest of this year, really important stuff. Obviously, there's the quarterly performance of DAYBUE that we're going to see heading for that guidance of between $380 million and $405 million of sales, which will mean $62 million-$67 million royalties to us. We're going to commence that trial for PMS, incredibly important, mid-year.
We're going to seek alignment with FDA as we did with Phelan-McDermid syndrome on Pitt-Hopkins, Angelman, and HIE. Finally, looking to advance those other indications I talked about, again, with this judgment on Prader-Willi alongside that. Huge amount achieved, but a huge amount ahead of us. The team's highly motivated to do that. I think aligned with shareholders from a financial point of view now as well to achieve these things, which we think is going to drive shareholder value. I will stop there. Thank you very much indeed.
Okay. We'll now proceed to the formal business of the meeting. I'll take the notice of meeting, including explanatory memorandum as read. Before moving to the resolutions to be considered today, I'll briefly outline procedures for today's meeting.
Please note that only shareholders, proxy holders, or shareholder company representatives are entitled to speak at this meeting. Voting on the resolutions will be conducted by way of a poll. The results of the poll for each resolution will be published on the ASX after the meeting. For those attending the meeting in person, you can cast your vote by filling out a paper voting card. If you have any questions, please see an MUFG Corporate Markets team member at the registration desk outside this room. For those shareholders participating in the meeting via the online platform, you can cast your direct vote using the electronic voting card received when online registration is validated. Please refer to the virtual annual meeting online portal guide or use the helpline specified. Following the formal business, general business questions will be taken.
If you're attending the meeting in person, you would have been given an attendance card when you registered on arrival. If you have a yellow voting card, you are a voting shareholder, proxy holder, or corporate representative and have chosen to vote using a paper voting card. You are also entitled to speak at this meeting. If you have a blue card, you are a non-voting shareholder. While you are entitled to ask questions and make comments, you are not entitled to vote at this meeting. If you have a red card, you are a visitor, and you are not entitled to speak or vote at this meeting. If anyone with a yellow or a blue card wishes to speak, please raise your hand at the appropriate time and identify yourself to me before asking me your question using the roving microphone.
For those who are participating via our online platform, you will be able to submit questions by registering as a shareholder or proxy holder and clicking on the Ask Question tab. You will have the opportunity to submit an online question or a verbal question by selecting the web phone option. Please follow the prompts or refer to the online guide for instructions. I encourage shareholders who have questions to send their questions through as soon as possible. I will consider the questions submitted online and by web phone after I've taken questions from the floor. The first item of business is to receive and consider the annual report for the year ended 31 December 2024. The annual report is not to be accepted, rejected, or modified in any way. This item of business does not require a resolution to be put to the meeting.
I'll now open this item for discussion. Would anyone like to address any questions to the company or to Diane Angus, the representative of Grant Thornton. Are there any questions from the floor? We have one here. There's a microphone coming.
Good morning, Chairman. My name is Peter Wray. I'm a shareholder in Neuren. I'm also holding proxies for the Australian Shareholders Association.
Hi, Peter.
Just a quick congratulations firstly. Thank you. And a good result last year. Looking forward to following the progress over the next year and hope that it's reflected in the share price too. I reflect your views that the share price should be higher than it is now. Also, just thank you for holding a hybrid meeting as well. It's good to see that shareholders who are not able to make it here physically are able to participate in the meeting.
Just a quick question in relation to remuneration. I understand the company is listed, sorry, is incorporated in New Zealand and accordingly probably does not need to include a remuneration report in its accounts here. Would the board consider providing? There is some limited detailed information in the back of the annual report. Given that the shares are listed in Australia, would the company, the board consider providing more detailed remuneration information for the directors and the senior executive more along the lines of a basis that is required here for Australian listed companies under Australian corporations law?
Yeah. Thanks, Peter. That question does come up fairly regularly at the annual shareholder meeting each year. We keep an open mind to it. I personally do not think that the disclosure is lacking. We are a pretty small, lean enterprise. We try to eliminate extra effort where we can.
While I think my takeaway would be we'll keep an open mind to it, at the moment, we're not proposing to change how we report. We are also, well, the executives and the team are heavily driven by the equity component, which we've announced separately some color to. I think that gives a little bit of extra information beyond the annual report. Thank you for your question.
Thank you.
Are there any other questions from the floor? There's one at the back, Geyear
rry.
Hi, my name's Mark Swindon. I'm a shareholder. Of course, we're all concerned about the share price. Can you tell us what other strategies are at play by the board to drive the share price other than the soon-to-be-completed share buyback?
Mark, if it's okay, can we come back to that question when we, right now, I just want to cover anything for the annual report. We've got a session at the end for open questions, and I'll come straight to you at that point if that's okay. Are there any other questions from the floor on the annual report? Don't think so. Are there any online or by phone? There are none. Okay. We've received, or we haven't received any further questions. As mentioned, there's no resolution required. We'll now move on to the resolutions of the meeting. Valid proxy votes have been received representing between 32-35% of the issued share capital. The proxy votes received are shown in the slides. There will be an opportunity for shareholders online through the virtual meeting website to ask questions on each resolution being put to shareholders.
Now moving to the resolutions, as mentioned, I propose to call a poll on each of these resolutions. Resolutions one, two, three, and four set out in the notice of meeting are ordinary resolutions and as such must be approved by a simple majority of the votes cast by shareholders entitled to vote and voting on the resolution. Resolution one concerns the re-election of Diane Angus as a director. Diane has served as a non-executive director since 2018. I now move that Diane Angus be re-elected as a director of the company. Firstly, are there any questions from the floor? Doesn't appear to be the case. Are there any questions on phone or online? No? Thank you. Would you please now select for, against, or abstain for resolution one on the voting card? Resolution two concerns the re-election of Jenny Harry as a director.
Jenny has served as a non-executive director since 2018. I now move that Jenny Harry be re-elected as a director of the company. Are there any questions from the floor? There are none. Are there any on the phone or on web services? No, there are none. Thank you. Please now select either for, against, or abstain for resolution two on the voting card. Resolution three. In accordance with section 207S of the New Zealand Companies Act 1993, resolution three seeks authorization for the board of directors to fix the fees and expenses of the company's auditor. I now move that the board of directors is authorized to fix the auditor's fees and expenses. Firstly, are there any questions from the floor? There are none. There are also none online or on phone. Thank you.
Would you please now select either for, against, or abstain for resolution three on the voting card? Resolution four concerns the approval in accordance with listing rule 10.17 to increase the non-executive director fee pool from 500,000 to 750,000. I now move for the purposes of listing rule 10.17, the maximum aggregate amount of director's fees that may be paid to the company's non-executive directors per annum be increased from 500,000 to 750,000. Firstly, are there any questions from the floor? We have one here, Gerry.
Peter Wray, again. Just wondering if you could just give a quick background as to the increase in the director fees. Thanks. I know there's a write-up in the notice of meeting, but perhaps if you could just give a bit more of an explanation, thanks.
Yeah, sure. Thanks, Peter.
Firstly, there's no intention in the short term to change what we're paying out of that fee pool. It's not to come back with some large jump in what we're getting paid. The intention is to give flexibility for the future. We're a small board, and some of us have had a reasonable amount of time on the board. In the future, when we need to manage a rotation of directors or maybe to strengthen in a particular area, we've got some flexibility to do that. It's purely housekeeping, looking a little bit further ahead and in the near term, not trying to draw attention to something that's on the near-term horizon. Okay, thank you. Are there any questions online or on the phone? There are not. Thank you. Would you please now select for, against, or abstain for resolution four on the voting card? Okay.
We've now moved to general business questions. Perhaps, Mark, if I could pick up on your question, which essentially is, what else is the board considering beyond pursuing what we've spoken about here, I guess? I mean, in truth, nothing matters more than progressing now to 591. Anything else we talk about is, in my opinion, of lesser importance. That said, we did in November launch a buyback, and we've had questions as to whether we might do more of a buyback or consider a dividend or some other capital management, given that we do have a very healthy bank account at this point. The board considers regularly whether we're holding sufficient cash to pursue the options in front of us.
What we've done with the first of the NNZ-2591 indications today, in fact, the first time we've announced what that investment looks like, 160 patients between $80 million and $90 million. We have in front of us many other indications that we will, probably in the next 6 to 12 months, know more precisely what that investment will mean. The royalty income, which we now have much more confidence, much more predictable against those future indications when we firm up what they will cost, what investment is required then, we may consider other capital management options at that point. Advancing the products, pushing through phase three, continuing to assess whether we're holding surplus cash are probably the key things that we look at.
Of course, we remain open to, and we are active in talking with many partners and many possibilities for the company, all of which come into the boardroom and will be shared with our shareholders at a time when that might make sense. We believe plan A is the right one. Push hard with 2591 on multiple fronts and manage this very fortunate position we have with our cash carefully from here. That is our plan. Are there any other questions from the floor? It is coming, Adam.
Adam Nettleton, long-term shareholder. Very happy shareholder, I might say, notwithstanding this year's share price performance. I just quickly want to extend my thanks and congratulations to the entire board for your amazing work. I have got a lot of questions, but I have condensed them down to four, if I may. Do you want them one at a time?
I think how many you got, Adam? Just give me a four. All right.
We get a chance to see the preclinical data for HIE? Can I ask? When will we get a chance to see the preclinical data?
Yeah, I mentioned that some of it is historical, which has already been published, actually. Right. The more recent stuff hasn't been published yet. Yes, you will. I am not going to tell you exactly when yet, but again. It's like, you know, I'm interested in that side of the business. I'm fascinated to see it. It looks, I mean, that is an extraordinary indication if that one got up and going. Can you give us a quick update on the Canada pricing negotiations? Are you able to comment on that or no?
Yep. Sure.
In fact, let's incorporate, there's a question coming online, which is exactly this. Let me just read it out. Can you please provide an update on the reimbursement authorities? Your DAYBUE in Canada, are you optimistic on the process and what are the implications for a negative final decision? Just so that everyone understands the situation, DAYBUE has been approved by the regulatory authority, the equivalent of the FDA in Canada. Now there's a process where you have to seek approval for reimbursement in the public market, not in the private market, but in the public market. The initial draft response from the reimbursement authority was to deny reimbursement, and they set out all the reasons why. My understanding is that that's certainly not unusual. That often happens.
What usually happens from there is that you request a re-review and then you go back into a loop where you can provide a response to their initial draft publication and obviously have new arguments. My understanding is that will happen for DAYBUE. I think it is about a three-month turnaround. From what ACADIA said, I think they are confident about that process, but you do not know until you get to the end. We shall see. Now that you know the numbers needed for the Phelan-McDermid phase 3 trial, can you narrow down the timeframe that that trial may be completed in or not? Yes. I mean, I will stick to the guidance I have given before that the reality is with all these trials, you do not know until you start enrollment and how fast enrollment is.
I think for everyone now, there's a very good yardstick out there, which is the Rett syndrome trial. I've showed you how similar this is to that. ACADIA took two years from start to results. That broadly is about 18 months enrollment, three months treatment, three months of analysis. That's broadly how you get to two years. I think that's the best base case that everyone should have. COVID was around during that enrollment period, which hopefully we won't face something like that. Again, until we get some experience, I think that's the base case everyone should have. Yeah. My last question. Have your recent discussions with the FDA for Phelan-McDermid, have they fast-tracked the progress for Pitt-Hopkins in particular in any manner? They have certainly, I think, in our minds, brought clarity to that process.
I think we always felt that would be very instructive for Pitt-Hopkins. So we now know what we need to go to FDA with. It does not really fast-track the development process. We have got to do the same thing, I think, with them as we have done with Phelan-McDermid, but it certainly gives us clarity, which is a big advantage, obviously, going into the meeting. Great.
That is all for me. Thanks very much, Jon and Patrick and the board.
Thanks, Adam. Are there any other questions from the floor? Are there any other questions online or on the phone? There are not. Ladies and gentlemen, that concludes the formal business of the meeting. Shareholders participating via the virtual meeting website should now have submitted their votes. If you are intending to vote, you will be able to finalize and submit votes up until five minutes after the meeting ends.
The results will be announced to the ASX after the conclusion of the meeting. I now declare the meeting closed. Thank you for your participation today. For those in the room that would like to join us for a light refreshment, please do so just outside near the registration desk. Thank you for your attendance today.