Idorsia Aktie

Good day, and thank you for standing by. Welcome to the Idorsia Pharmaceuticals Daridorexant Pediatric Insomnia Results Conference Call. [Operator Instructions] Please be advised today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Kevin Boss. Please go ahead.

Thank you, Nadia. Good afternoon, and good morning, everyone, and welcome to today's webcast. We are here to discuss the positive results of the Phase II study of daridorexant for children with insomnia disorder, which we announced yesterday. On the call today, we have Jean-Paul Clozel, Chairman of the Board and Interim CEO of Idorsia; Martine Clozel, our Chief Scientific Officer and Head of Research; and Alberto Gimona, Head of Global Clinical Development and Medical Affairs. They will provide context on our daridorexant program and walk you through the key results from the pediatric study. Following their remarks, we will be happy to take your questions.

Next slide. The information presented today contains forward-looking statements. You have therefore been appropriately warned about the risks and opportunities associated with investing in Idorsia. Importantly, to today's presentation, daridorexant for pediatric use is investigational and not approved or marketed in any country. Next slide.

With that, I'll hand over to Jean-Paul.

Good morning, good afternoon to all. I am very happy to have the opportunity to join the call today and share some very exciting results. While we still have a lot of work to do in order to analyze the wealth of data generated, the top line results are very impressive. I hope you understand that we will share the detailed results at upcoming congresses and in peer-reviewed publication. To be able to protect publication in top-tier journals, we have to restrict what we share today. I am sure that you will agree with me that these results are very exciting. And I think what I also wanted to emphasize is that the fact that these fantastic results are really due to the very specific properties of daridorexant, which was chosen after synthesizing more than 25,000 products. And Martine will explain to you why this drug is so different and so exciting.

Next slide, please. In this study of 165 children suffering from chronic insomnia with or without neurodevelopmental disorder, we see a major improvement of sleep, particularly in those children with neurodevelopmental disorders. This alone is exciting. But beyond insomnia, the data suggests that orexin may play a broader role in children with neurodevelopmental disorders, potentially opening an entirely new therapeutic avenue for these patients.

Next slide. We understand since [ Sakurai ] in 2007 that orexin, which is produced by only a very small number of cells in the brain is a central player in wakefulness. The very same year, we published in Nature Medicine that dual orexin has receptor antagonist, which we call DORA, induce sleep and a very good quality of sleep. Now we know that insomnia is characterized by another active wake signaling. And that DORA's are a very good way of treating insomia to inhibit the [ overactive wake signal ] by blocking the 2 orexin receptors instead of depressing the brain to induce artificial sleep as most older drugs in insomnia were doing.

Next slide, please. But not all antagonist of the orexin system are created equal. We have worked relentlessly, even stopping the development of our first dual orexin to arrive at the optimal molecule. As Jean-Paul was telling, after 25 years of research, more than 25,000 molecules designed and synthesized are dual orexin and guided by the revolutionary work of computer modeling, we achieved what we were aiming for in our drug discovery and data. An antagonist of both orexin-1 and orexin-2 receptor, blocking both receptors with equal potency. With the rapid onset of action and the duration of action long enough to cover the night, but short enough to be divide of carryover effect even at the optimal dose for sleep. That's the best possible profile for a sleep drug. By that research goal, we wanted to avoid the pitfalls of molecules for insomia with suboptimal and too long pharmacokinetics, giving either the risk of carryover some somnolence in the morning or a sub-optimal efficacy when trying to avoid the disturbing risk of morning and daytime insomnolence by reducing the dose. QUVIVIQ has basically the perfect profile. As we can see on the right of this slide, fast absorption, fast decline and no accumulation over time.

Next slide, please. Daridorexant, QUVIVIQ, really surpassed our expectations in adults with insomnia both on efficacy and on safety. It is an extremely effective drug, within adults, 1 hour more of more of sleep at night, improving both sleep induction and the maintenance of sleep, giving also a better quality of sleep, restoration of a physiological sleep pattern with, in particular, more sleep. Daridorexant works in all periods of the night with the largest efficacy in the fourth quarter of the night.

Next slide, please. And yet, when we were checking if there was any carryover effect in the morning, there was none. The highest dose here in green of 50 milligrams per night did not induce sleepiness in the morning. To the contrary, thanks to the much better night and the exceptional pharmacokinetic profile of daridorexant, morning alertness was improved at 50 milligrams.

Next slide. I believe that the better night sleep in combination with no residual somnolence and the equilibrated antagonism of both orexin receptor is 50-milligram also improves the daytime functioning so well. Using the insomnia daytime symptoms and impact questioner, so-called [indiscernible]. We found that QUVIVIQ 50 milligrams improved all 3 domains: sleepiness; alert cognition; and mood and all the 14 questions of those domains with an increasing effect over time. This makes QUVIVIQ the only therapy to demonstrate significant improvement in data and functioning in patients with insomnia.

Next slide, please. Finally, as already mentioned, a very good safety and tolerability after chronic daily repeated administration, even on very long term.

Next slide. You will now see that once again, we are impressed by what this molecule brings this time to children with chronic insomnia as young as 10 years of age. The burden of chronic insomnia is substantial, especially in children with neurodevelopmental disorders, such as autism spectrum disorder, or ASD, and attention-deficit/hyperactivity disorder or ADHD. It profoundly effect the quality of life of both the child and the family, yet there is currently no FDA-approved medication for pediatric insomnia in the United States.

Alberto will now take you through the study design and these very important results. Alberto, next slide, please.

Hello. Thanks, Martine. Dear all, I'm happy to present to you the results of daridorexant study in children. As a note, I think Idorsia was the first company to start the program in children with the DORA. And given the daridorexant properties that Martine has just described, we actually were very eager to negotiate a program [indiscernible], and we did it with FDA and PDCO, with EMA. But first of all, let me thank the investigators together with the children, the caregivers who invested time to advance the science. And I'm happy to say that their time and effort was eventually very well awarded.

Next slide, Slide 13. In this slide, you see the study design is a double-blind, placebo-controlled dose-finding study, where children were randomized to 3 doses. Please note, these are the same doses studied in adult, 10, 25 and 50 milligrams. The children, the parents had the burden of spending 3 nights, 2 at screening and 1 on day 1 at the sleep lab to undergo polysomnography, from which the primary endpoint was derived. And this is an important feature of the study is polysomnography and 3 cumbersome nights, but the children and their caregivers did it. One question you may see on the slide is that on day 1, the primary endpoint is measured. So it's baseline to night in sleep lab, day 1, there is a sleep lab, again. But why on day 1 and not at the end. Indeed, because health authorities were concerned about the discontinuation rate in children, particularly with those nights at the sleep lab. So they wanted to minimize the risk of missed data points by getting the primary endpoint as early as possible during treatment. And actually, this was probably driven by the experience they had with previous studies. But indeed, in our study, we have only 1 child that did not remain in the study until the end of the treatment period, giving the first hint that the drug was very well tolerated and actually, they indeed like the drug because they continue to stay in the study.

Next slide, please, Slide 14. So as mentioned, the primary objective was the valuation of the total sleep time by polysomnography. Again, the study investigated 3 different dose, and the main point is the dose report -- the evaluation of the dose response instead of the [ per ways ] comparison to placebo. The study was sized to show those response.

Next slide, Slide 15. And here, you see the stratification in the study, which is an important innovative feature of this study that I'm proud we were able to negotiate with the health authorities. In effect, that include patients or children with narrow development disorders as well as children without comorbidities. And again, this was done to accommodate both EMA and FDA. In the middle, there is also a group of patients with subthreshold ADHD ASD, which means that they did were not diagnosis, but at screening, we have tools, recognized tool to screen for symptoms in size of ADHD and ASD, and they did not meet the formal definition. Eventually, we were able to agree with both FDA and [indiscernible] that those response was evaluated under overall mixed population.

Next slide, Slide 16. You see the demographic characteristics in this slide. And interestingly, there was 20% of children were down -- with age 10 and 11, which, in my opinion, honestly, is a great -- was a great achievement by the study team in considering and the investigator as well to convince the parents or the caregivers and the children to stay in the sleep lab for 3 nights. Another interesting feature is that we have 50-50 split between males and females. It's slightly different to the adult population where we have approximately 2/3 women and 1/3 man. The body weight is represented at the bottom of the slide, and you see that this expect -- as expected in this population. But actually, I would like to draw the attention, it's nothing to do with the study. But indeed, you see that the range of body weight were exceeding 100 kilograms for children in all treatment groups. So there is overweight and obese children in line with the increasing burden of this disease also in the pediatric population.

Next slide, Slide 17. Baseline disease characteristics, the average time from the diagnosis of insomnia was approximately 4 years. And you see the 3 characteristics that define insomnia and they are difficult to get to sleep and maintain a sleep during night that were reported basically by all children. And actually, early morning awakening was a little bit less represented. But the most important feature of this slide for me is the fact that, as mentioned, we had already 30% of children with the diagnosis of autism spectrum disorder and ADHD, attention-deficit hyperactive disease. On top of this 30%, there was an additional 20% with subthreshold ADHD and ASD, meaning patients with -- children with feature symptoms but didn't meet the diagnostic.

Next slide, Slide 18. I'm happy and proud to share that the study was successful and highly statistically significant dose response was observed. You see the p-value over there. In this study against the first regulatory study with DORA in children. Importantly, and the different versus placebo, at the high dose, the 50-milligram high dose with even nominally statistically significant difference from placebo. Again, this was not a requirement of the study, but the effects of so strong that we had also a statistical significance there. But further, the effect was particularly impressive. Actually, I would say with -- I haven't seen it earlier on with unprecedented increase in TST versus placebo in children with neurodevelopment disorders. Of course, this is -- we should be still be cautious because this is a dose finding study. But really, the results you will see when we publish are impressive. Let me say that there are still so many data that we need to analyze and properly interpret that we cannot say more. But -- while any conclusion cannot be drawn, I'm really excited about what we have seen beyond sleep. Here is a total sleep time, but we have other measures in children with the neurodevelopment disorder, that actually surprised me and excite me, and we are going to further analyze to put into a very nice publication that shows -- this data show that we may have potential impact on the disease itself and not just on insomnia.

Next slide. Slide 19. I This, for the moment, what was already is -- a great achievement here of this study is that we can say already that the safety profile at the same dose tested in adults. So we have children with the body weight. I mentioned the high range, but I would also like to mention the lower range, which was about 28 to 30 kilos, even the highest dose 50-milligram was well tolerated and actually, there is no dose response on any adverse event, but also similar to what we have observed in adults also on event -- events of special interest such as excessive daytime sleepiness, suicidality or drag abuse potential, all adjudicated blindly by an independent panel. The word here, why we adjudicate some events by a panel because we don't want to miss any signal. And here, again, shows and make it robust to the fact that we did not see any dose response of any of these events and especially no event at all most of these categories, including drug abuse.

Next slide, Slide 20. It's a very boring slide. And I will say thanks to whoever, but there is nothing here. Nothing really relevant when looking at adverse events reported by the children. And then you see all the adverse event reported in the population are in 1 table, which is quite exceptional. And you can see notice for -- and reaching to what Martine said earlier on. So we have very few adverse event 1 to 3 patients across group, including placebo, with somnolence and fatigue, which is the -- what we usually review when we look at the data in insomnia. Again here, no dose response. So eventually, the weight tolerability and safety to file observed in the adults seems concern -- confirming children. Again, same exact as [indiscernible].

Next slide. Slide 21. You have seen earlier the morning sleepiness, or actually, the name is not really reflecting what it measure. Actually, it's morning alertness reporting in adult population. Again here, we showed a similar measure in children. Again, the green bar is daridorexant at top of those and the blue is placebo. On top, you see the baseline and you see at week 2 after only 2 weeks, you observed that an increase in -- versus baseline of daridorexant 50-milligram and also an increase versus placebo. Again, the highest dose, we do not observe any sleepiness in the morning, rather a better, more refreshed pediatric population. And you see the scale from 0 goes from extremely tired to 100 [indiscernible].

Next slide, Slide 22, which is going to be my last slide. So with this data, what are the next steps. First of all, I'm looking forward to discussing this data with the health authorities, the PEDCO for EMA and the FDA to agree on a path forward to bring daridorexant into the children with chronic insomnia. We have, as some of you may remember, we have a bit in Europe, and we need to discuss also with EMA, the optimal path forward for the younger children cohort at -- below 10 years of age from 4 years to 10 years. This is what is summarized on the left of the slide. But equally, actually and really more exciting, we need to fully evaluate the surprising results that we see in NDDS, neurodevelopment disorder subgroups and then discuss with the health authorities about the potential program from children with NDDS beyond the treatment on this insomnia. But maybe here, the most relevant part, already immediate relevant part is that actually, this data is also relevant for adults. Insomnia is a -- we have a broad indication for insomnia in the U.S. and in Europe. And there are already many millions of patients with ADHD or ASD in the population in the U.S.

With that, I will hand back to Jean-Paul with the next slide, Slide 23. To you, Jean-Paul.

Thank you, Martine. Thank you, Alberto. I have to say that I'm really very happy when I see these results because Idorsia went through difficult times, and really, I want to thank all the collaborators, all the Board members, everybody who stayed. Without them, without this perseverance, we would not see today this data which in my mind will -- and you will see after the publication really represents a scientific breakthrough. These results show once again that daridorexant is an outstanding drug and they present a great opportunity for Idorsia. First, the clean safety and tolerability profile in children as young as 10 will undoubtedly strengthen confidence in QUVIVIQ among prescribers treating adults. Second, our continued development in the pediatric population should influence the descheduling process with the FDA and DEA.

Third, the unmet medical need in pediatric insomnia is substantial. Millions of children experienced chronic insomnia that profoundly affects daytime functioning, mood and cognitive and physical development. Remember, daridorexant is the only DORA currently being investigated in the pediatric population, positioning it to become not only best-in-class for adults, but potentially first-in-class for children.

Finally, the emerging data on neurodevelopmental disorder could unlock an entirely new therapeutic domain for daridorexant beyond insomnia. And we look forward to initiate discussion with health authorities on the data. As soon as we secure presentation at the high-impact congress and scientific publication in a high ranking journal, we can go, and we will go into more detail.

Many thanks, Jean-Paul. With that, Nadia, I think we can open the lines for questions.

[Operator Instructions] And now we are going to take our first question, and it comes to line of am Raghuram Selvaraju from H.C. Wainwright & Co.

Congratulations on this very exciting data. I was wondering if you could provide us with some additional granularity regarding what's the scope and nature of clinical development for a drug like daridorexant might look like, in the context of neurodevelopmental disorders, particularly autism spectrum disorder and how the efficacy endpoints in such a context might change relative to what you would typically use like total sleep time, for example, in the insomnia setting specifically.

And also, if you could give us some additional data on how the market opportunity, the total addressable market could change for daridorexant if it were granted an official label some years down the line, for example, in neurodevelopmental disorders, including but not limited to autism spectrum disorder.

Thank you, Ram. Maybe, Alberto, you take the first question, and then we hand over to Jean-Paul for the second question.

Yes, of course. I think as we will -- it's too early to look at what is the development plan that could be in neurodevelopment disorders, autism ADHD. Of course, the main hypothesis is emerging is that, okay, there is no doubt, this is my personal opinion, there is an effect in insomnia in this population. However, the new program will not look at insomnia in patients with neurodevelopment disorder rather potentially bringing the treatment of the disease is what also Martine was alluding to. And in that case, of course, the endpoint will be different compared to what we have now with TST or other measures of insomnia. So we will -- we may target directly the disease. And we have -- basically there are some scales that we can use and can be discussed with the health authorities. There is an EMA guidance, for example, on autism. so I'm not sure that the answer completed the first question. Kevin, tell me if I missed something.

That's fine. Thanks, Alberto. Then we can address the second question, Jean-Paul.

Yes. I think I have some numbers. I'm not speaking about commercial market, but the clinical need. I was turned first in adults. And as Alberto said, these adults today with insomnia can be treated with daridorexant. There is no exclusion from these patients. And I wa stunned done by looking that there are about 15 million adults with attention deficit disorders and about 25 to -- up to 50% of them have insomnia. So 7 million, if you want an average. 7 million of patients with ADHD, adults with insomnia. With intellectual disability or development disorders, 2.3 million adults with 85% prevalence of insomnia. And in autism, it's 5 million adults with autism today, and I would say, from 32% to 72% according to the publication. So about 50%, let's say, as an average, have, insomnia. So this is, frankly, a stunning number in adults. Now in children, of course, and I'm just speaking about the U.S., and I think that you could about -- multiply, have the same numbers in Europe. But focusing on the U.S., there are, in children, 5 million children with attention deficit -- or sorry, with hyperactivity and 25% to 50% of them have insomnia. There is -- there were 9 million children with intellectual disability. And they nearly are -- 90% have insomnia. And autistic children, there are about 2 million children. And I would say a majority of them have insomnia. So you see that -- even if we would take insomnia alone, there is a huge market in the U.S., and this is why I'm focusing on the U.S. number because there is no treatment today. So you see that there is a very big number of adults and children within insomnia, but also, of course, without insomnia. And as we mentioned, now we are going to really evaluate and certainly initiate a program in these patients with MDD. So I hope I answered the question.

I think you're on point, Jean-Paul.

Please, go ahead, Ram?

Yes. Sorry. I Just wanted to point out that as many in the audience may already know, autism spectrum disorder is growing at an unprecedented rate among neurodevelopmental disorders. And by some estimates, has increased by 175% in pediatric patients over the course of the past 2 decades. So I think that's an important thing to note. Two other very quick items I wanted to touch upon, if I may. One is with respect to whether or not you intend to seek additional prosecution of further patent claims around daridorexant to broaden the IP estate based on the observations that were made from the Phase II pediatric insomnia trial. And the other is from a competitive landscape perspective. If we look at the DORA class, and the unique attributes of daridorexant from a safety and tolerability perspective, is it your view and your expectation that because daridorexant seems to be uniquely safe and well tolerated, particularly for use in children as this Phase II trial showed that this might erect a competitive moat around it that will enable it and it alone to be applied in the pediatric setting and in the neurodevelopmental disorder context. Whether or not its ultimate activity lies solely in the domain of improving sleep or extends to other efficacy parameters.

So we -- we certainly have very unique properties by having this optimal pharmacokinetics and the data on -- data and functioning in adults are very, very compelling. And you see now -- you have only a glimpse of the results we are progressively discovering in the pediatric study, but we see this dose-dependent increase or increase at the highest dose, which is quite really surprising both in adults and now in children of an increase in morning alertness. And I think that we have really a perfect profile for children, and the safety and tolerability, which as you have seen are amazing, including a total absence of signs of abuse or withdrawal or addictive signs. So we have really a drug which is really perfectly suited for children and the result in sleep and [indiscernible]. So yes, of course, we are serving and taking care of the protection of the data, absolutely.

Yes. We have worked very actively on protecting this data. Of course, that's something which is key, and we have all the -- we have been active in the coming -- in the last weeks to really protect this new data. What I wanted to say that we had daridorexant, and we knew that we had an active drug, but we did not have the ideal drug. As Martine said, it took us 10 years and 25,000 new drugs in order to discover daridorexant. And it's only because daridorexant has it's unique pharmacokinetic properties, it's unique binding that we can achieve this data. It was really worthwhile to wait 10 years to work so hard for the chemist to get there. And I really believe that without these properties, it will be extremely difficult to go in children, for example, of a very low weight or to avoid the somnolence in the morning because of the pharmacokinetic characteristics that you need to get to this profile.

Maybe -- Alberto here. If I can add 2 words actually, I think in the competitiveness, I think that we have -- given what Jean-Paul and Martine has said, I can just add that from a development perspective, we are the -- in the adults and now it seems to be confirming children that it's the only one with a dose response on efficacy and no dose response on safety. And that can be seen easily in the FDA reviews of the data, and we have done exactly the same analysis with daridorexant that they did for lemborexant, for example. And actually, we were able to demonstrate that we don't have a dose response on safety. That's why they translate clinically the profile that Martine and Jean-Paul were highlighting from a scientific perspective. Sorry, just a comment.

Thank you, Ram, for your comments. Nadia, next question.

And the next question comes line of Joris Zimmermann from Octavian.

Joris Zimmermann from octavian. I have a follow-up question on the regulatory path forward. You mentioned that for the neurodevelopmental disorders, it might be a bit early, but I was wondering if you could share the expected next steps in terms of the general pediatric insomnia patient population? Or if my understanding here is indeed correct that you pursued the 2 indications independently? And if so, what your expectations are around the needed trials, time lines and if possible, already on the costs?

And then second question on the potential. I was wondering how do you assess the potential from the pediatric indication versus the potential that you could see from the potential halo into the adult population?

Thank Great. Thanks, Joris. Alberto, do you want to take the first question?

Absolutely. Again, as I mentioned earlier, it's too early. But indeed, the next steps will be to discuss with the health authorities. So for -- and you're right, we may -- we will -- need to pursue general insomnia, and with the data that we have in Phase II, although the data being so good that maybe we can discuss what are the further steps. But certainly, the bottom line is to get an agreement on path forward from both health authorities, with the minimize -- the idea is to minimize the number of patients or studies to be done. And the NDD is completely different -- separate. Again, we are not targeting NDD insomnia in those patients in those children, rather the symptoms or the feature of their disease. And for that, we need to get discussion. Again, there are only -- we are guided only by the guidelines for EMA at this point. And -- but we -- and there is no guideline from the FDA. So again, we need to use certainly specific scales and endpoints that are validated in for autism and then see what kind of studies the authorities request us to do. Again, I didn't answer very [ quick ], and I'm not answering about cost or time lines at this point because it's really too premature.

To answer your question on the repercussion for adults, I think, we have really a duplication or a replication of the amazing efficacy and safety profile in children. We knew daridorexant efficacy and safety at the same doses without dose adaptation in elderly, we are learning progressively that in patients with nocturia, as published, the efficacy on sleep also was replicated. Every time we are reproducing that this children study at the same doses as in adults with the amazing efficacy on sleep, particularly in the neurodevelopmental disorder subgroup are very, very impressive. And for that, I think, yes, it repercussion in the understanding of the potential in [ adult guideline ].

For the halo effect, how do we quantify. It's -- I would not be quantitative, but maybe qualitative. I think that what this data bring, if you can tell to a doctor that the really high dose, the higher dose, which can be -- which is allowed in adults has been given to children of 10 years old without any problem, I think it will convince them that this drug should really be safe in adults, I'm speaking. And really, you know that sleep drugs have always got a negative value because up to now, they had all side effects. So I think it's really going to help the marketing of today daridorexant in adults. But maybe the most important halo effect in adults with neurodevelopmental disorders because I think that when this data will be presented, you will understand why -- frankly, there would be only 1 drug to give to this patient when you see our data, and this is daridorexant. So -- and here, we are completely covered by the present label, both in the U.S. and Europe. So the halo effect for me, the most important is adults with neurodevelopmental disorders.

Thank you, Jean-Paul. Nadia, next question?

And the question comes from line of Sushila Hernandez from [indiscernible] Kempen.

This is [ Samreen ] on for Sushila. Congrats on the results. So first of all, I would like to go a bit more into your -- yes, the market that you were addressing. So how many of these 10% to 30% of U.S. children and adolescents that are impacted by insomnia do you aim to target actually? And which segment in the children -- in that market do you think would benefit the most?

And also a bit more on the future. So again, you said the financing is still preliminary, but can you tell us anything on whether the company feels sufficiently financed to conduct an extra study in pediatrics? And could you maybe expand a little on your current capital allocation priorities?

Thanks for the question. Jean-Paul.

I'm just saying that it's a little bit different between Europe and the U.S. for the children, I think that there are a lot of patients with insomnia -- children within insomnia in the U.S. who are treated. And this is not as a big number in Europe. So the market is certainly much bigger in the U.S. And I think that we have not really -- we have just got the results, and I would not be able to guide you on the potential market, but it is very big. And I think that if we consider is in the U.S., it's very big. Of course, neurodevelopmental disorders is also a very big market, but we need to do additional studies. And -- but I really -- when you speak about the cost of this study, first, these studies are just a questionnaire. This is not like many in many studies where you really need a CT scan, MRI, very expensive. Here, it's simple -- it is going to be a simple questionnaire and observation by the doctors, by the parents, by the caregivers. So these are not very expensive studies as you could imagine in other neurological problems. That's number one. The number two, I really hope that this halo effect that everybody believes is going to happen, we'll pay for it.

Nadia, next question.

And the question comes line of Justine Telliez from Kepler Chevron.

Congrats on this promising data. One follow-up question again, please, coming back on the potential program you aim to initiate in NDD patients. Could you please elaborate on how you are thinking about the target population? Would this initially focus on pediatric patient, age 10 and above? Or could we also think about a broader approach over time, potentially extending into adult populations?

Thanks, Justine. Alberto, do you want to take that question?

Yes, of course. I start from the last part. Certainly, we will need at 1 point to do as a line extension potentially to look at adults assuming, we will be successful in the children pediatric population. For looking at the population, I cannot say much. But indeed, we -- one of the things that we are trying to target is really to identify a specific neurodevelopment disorder, not in general disorders, for which we have specific scale, which are agreed by the health authorities. So I would certainly say that at the end of the analysis that we are doing, further analysis that we are doing on the children that we have between ASD and ADHD, 2 neurodevelopment disorder that we have in our study, we will be able to choose 1 and then get -- as Jean-Paul said, not a simple study, never simple study in this disease. But certainly, not in insomnia, but looking at the symptoms and therefore, using questioners. Did I answer your question or...

Yes, yes, you did.

Thanks, Justine. Are there any further questions, Nadia?

There are no further questions for today. I would now like to hand the conference over to the management team for any closing remarks.

Thank you, Nadia. If there are no further questions, we will conclude today's call. Thank you all for joining us today to look at these exciting results. Nadia, please close the lines.

This concludes today's conference call. Thank you for participating. You may now all disconnect. Have a nice day.

Good day, and thank you for standing by. Welcome to the Idorsia Full Year 2025 Financial Results Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to our first speaker today, Srishti Gupta, CEO. Please go ahead.

Thank you, Nadia. Good afternoon and good morning, everyone, and welcome to our webcast to discuss the financial results of 2025. My name is Srishti Gupta, I'm the CEO of Idorsia, and I'll start the call today with an overview of the operational progress we made in 2025 and the exciting plans we have for 2026. I'll then hand it over to Arno Groenewoud, our CFO, to walk you through the company's financial position. We'll then take your questions.

Next slide, please. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties and other factors. These may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements.

Next slide, please. We entered 2025 facing significant financial pressure, but we leave the year stronger and more focused. 2025 was a year of stabilization and preparation. We reinforced our balance sheet, delivered disciplined commercial execution and positioned our pipeline for decisive milestones ahead. Most importantly, we continued advancing medicines that address meaningful unmet needs for patients.

Our Idorsia-led QUVIVIQ sales for 2025 have more than doubled compared to 2024, rising from CHF 60 million to CHF 134 million, just above our target, which we upgraded in May last year. This performance was a result of strong commercial traction and growing demand for QUVIVIQ in Europe and Canada, the stabilization and optimized model in the U.S. I will share more on this later.

Our non-GAAP operating results have improved from a loss of CHF 308 million to a loss of CHF 100 million. Key to this operational recovery has been our commercial strength paired with cost control. Arno will share more on our financial performance later.

Next slide, please. Idorsia represents a rare combination of valuable assets. We are a commercial stage pharma company with 2 products that have blockbuster potential. We also have a rich pipeline of first or best-in-class medicines.

We have a clear path to making QUVIVIQ the standard of care in insomnia. In parallel, we are actively engaging in partnership discussions to maximize the value of TRYVIO/JERAYGO and change the treatment landscape of uncontrolled hypertension. We also have plans to advance our innovative pipeline, leading where we can and partnering where we should.

Next slide, please. Let's start with QUVIVIQ. As you know, QUVIVIQ is a best-in-class dual orexin receptor antagonist. It works by suppressing an overactive wake signal rather than sedation as some older drugs tend to do. As a result of this mechanism and the best-in-class pharmacokinetic properties, we can confidently say that only QUVIVIQ offers restorative sleep and revitalized days.

Before we talk about the commercial performance of QUVIVIQ, it's important to ground ourselves in the patient experience of insomnia. Insomnia is not just the loss of a night's rest and it does not end when the night is over. It infects the entire next day.

Patients describe difficulty focusing, feeling emotionally depleted and struggling to keep up with work and family responsibilities. What they value most is a treatment that helps restore their ability to function during the day. That next-day benefit is what matters to patients and it's central to how we think about addressing this condition.

Next slide, please. We continue to expect sales growth of QUVIVIQ in 2026 as we guide to sales of around CHF 200 million, but this is just a step on our path to changing the treatment landscape and becoming a global blockbuster. We have a clear plan to achieve this. First, market expansion in Europe and Canada; second, unlock the true value of QUVIVIQ in the U.S.; and third, continue to build a global brand. Let's look at the progress we are making on this and what's ahead.

Next slide, please. In Europe, QUVIVIQ is the only pharmacological treatment for long-term management of insomnia disorder. Our 3-pronged approach to market expansion in Europe and Canada is proving very successful. First, we secure public reimbursement. Second, we invest in focused promotional efforts targeting psychiatrists, neurologists and sleep specialists. Finally, we expand into primary care with co-promotion partnerships.

Starting 2025, we had secured reimbursements in France, Germany, the U.K. and the private insurance markets in Switzerland and Canada. We continue to focus on reimbursement. And during the year, we obtained public reimbursement in Austria, successfully negotiated premium reimbursed price in Germany, entered price negotiations in Quebec, while submitting in Finland, and continuing our discussions in Spain.

This continues to be our top priority for additional markets. And in 2026, we expect to secure public reimbursements in Spain, Finland and Quebec while preserving our price corridor, submit in the Republic of Ireland and continuing discussions in Sweden, Italy and the rest of Canada.

Our promotional efforts targeting psychiatrists, neurologists and sleep specialists are leading to strong positioning in retail and hospital settings. We've expanded into primary care with co-promotion partnerships with Menarini in France in October 2024 and Germany in April 2025. And in February 2026, we added the U.K. This is having an incredible effect on our reach, and we continue to look for partners who have established presence and relationships with GPs in other countries.

The result of these efforts has been an outstanding trajectory, particularly in France, but closely followed by Germany, the U.K. and Switzerland when considering the relative market sizes. And that trajectory can continue. Just to highlight a few markets, demand in the final quarter of 2025 increased by 25% in Germany, 38% in Canada and 45% in the U.K.

Next slide, please. In the U.S., in 2025, we executed a targeted digital marketing strategy with Syneos Health to establish stabilize sales and maintain our core patient base. Going forward, ensuring more patients have access to QUVIVIQ remains a priority. To achieve this, we are advancing 3 key initiatives.

First, descheduling the DORA class, recognizing the safety in the same way as it is recognized in all other countries. This would simplify prescribing, facilitate access, expand the prescriber base and improve the patient experience, especially with regards to refills.

Second, we will conduct a streamlined label-enhancing clinical study agreed with the FDA to have QUVIVIQ's benefits on daytime functioning recognized in the U.S. label, again, in the same way as it is recognized in all other countries. This would reinforce our differentiated profile with physicians, patients and payers.

Third, we will be launching a direct-to-patient digital distribution model aligned with the evolving U.S. market and to increase access.

Next slide, please. In 2025, we continue to expand QUVIVIQ's global reach and change the standard of care for insomnia with new approvals, launches and strategic commercial partnerships. Several license agreements help cover markets shown here in green.

QUVIVIQ is available in Japan through our partner, Nxera, and they recently saw positive Phase 3 results in South Korea. Our partner, Simcere, has had a very strong uptake in China within the private setting with 300,000 to 400,000 patients treated within the first 6 months.

In June, we signed a licensing and supply agreement with CTS in Israel and more recently in 2026 with EMS in Latin America. In Brazil, the regulatory dossier has been submitted to ANVISA, marking an important step forward towards market entry in that region.

In red, you can see the next wave of planned distribution agreements focused on Central and Eastern Europe as well as the Middle East and North Africa. These partnerships are part of our strategy to broaden geographic reach efficiently. We expect to make further progress through mid-2026, and we'll keep you updated as these agreements are finalized.

Next slide, please. In 2025, we completed the recruitment into our pediatric study of daridorexant, enrolling children aged 10 to 18 with data expected in early Q2 2026. This will be an exciting readout that can pave the way for the first therapeutic option for children suffering from insomnia.

Pediatric insomnia is a major unmet need with an estimated 12 million children in the U.S. affected and no FDA-approved therapies available. Insomnia is more prevalent in children with neurodevelopmental disorders like autism spectrum disorders and attention deficit hyperactivity disorder, and our study includes these patients.

Daridorexant is the only DORA in pediatric development and, as the new standard of care, could revolutionize the treatment paradigm. We are particularly excited to share the results in the coming weeks and discuss the path forward with regulators.

Next slide, please. Our second approved product is aprocitentan, commercially available under the trade name TRYVIO in the U.S. and JERAYGO in EU. We secured regulatory approvals in the U.K., Switzerland and Canada during 2025. It is the only -- the first and only endothelin receptor antagonist approved for the systemic hypertension market. We are actively engaged in partnership discussions, evaluating global and regional deals. Our objective is to expand access for patients while creating value for all stakeholders.

Next slide, please. TRYVIO/JERAYGO is uniquely placed in the treatment landscape for difficult to control or resistant hypertension. Its efficacy and safety profile differentiates it to existing therapies and any of those in development. Our registration trial, PRECISION, remains the only hypertension study to enroll true resistant hypertensive patients, all on 3, 4 or more drugs when entering the study. Notably, there was no exclusion based on any antihypertensive drug class.

It also had the broadest inclusion criteria, including patients with eGFRs as low as 15. Aprocitentan delivered a double-digit blood pressure reduction of 15.4 millimeters of mercury in just 4 weeks, on top of a standardized triple therapy administered as a fixed-dose combination pill.

Aprocitentan has an excellent safety profile with low discontinuation rates observed over 40 weeks, no drug-drug interactions and no increased risk of hyperkalemia, hypotension or a decline in eGFR.

The FDA approval provided a broad U.S. label that indicates TRYVIO is suitable for use in all patients who are not adequately controlled on other therapies with the cardiovascular outcome benefit cited within the indication statement.

TRYVIO benefited from several important derisking milestones in 2025. In March, the FDA removed the REMS requirement, simplifying prescribing and distribution. Then in August, aprocitentan was incorporated into the updated comprehensive hypertension guidelines issued jointly by the American College of Cardiology and the American Heart Association, which was an important step in reinforcing its role in clinical practice.

Our recently published CKD subgroup data shows strong blood pressure lowering plus significant reductions in proteinuria, supporting TRYVIO as a compelling and differentiated option for these patients. Market access work for JERAYGO is also underway in Europe to support our partnering efforts.

Next slide, please. TRYVIO is currently being prescribed at more than 25 of the top hypertension centers as part of our focused prelaunch activities to generate on-market experience. In the clinical setting, we see consistent double-digit blood pressure lowering across subgroups, including CKD stages 3 to 4 with excellent safety and tolerability. We see prescriptions coming from key specialties, including nephrology and cardiology.

Early on-market experience is translating into increasing new patient starts and improving refill rates, reflecting growing physician confidence in the therapy. Prescribers report meaningful and reliable blood pressure control and comfort using TRYVIO across diverse comorbid patient types. TRYVIO's early real-world experience confirms and reinforces the pivotal trial data from PRECISION.

Next slide, please. Our U.S. label allows us to target patients with uncontrolled hypertension despite treatment on 2 or more therapies. Within this broad patient population, there are clear and identifiable patient subgroups that would be the natural initial choice for prescribers. These include patients who remain uncontrolled despite treatment with 3 or more therapies, truly resistant hypertension by definition. This is a group with significant unmet need and high clinical urgency.

Second, patients with uncontrolled hypertension and comorbidities where endothelin is known to play a role, such as diabetes and obesity. Third, there is a clear need among patients with uncontrolled hypertension and chronic kidney disease, including those with eGFR down to 15. In this setting, TRYVIO offers a differentiated option without the hyperkalemia risk or eGFR decline that often limits other therapies.

Importantly, our on-market experience shows strong uptake across these same patient segments. Notably, given the significant unmet need and clear medical value in these patient populations, the prior authorization process has been very smooth.

Next slide, please. Let's turn now to our pipeline. 2025 was a year of meaningful progress, laying the foundations for long-term growth. We are making deliberate focused investments to accelerate our most value-creating assets, supported by a leaner and more streamlined R&D organization. We have advanced our first-in-class immunology portfolio of 3 chemokine receptor antagonists.

The study for our CCR6 receptor antagonist is already enrolling in psoriasis with broad potential in T helper 17 driven autoimmune disorders. A study to show anti-inflammatory and remyelinating properties of our CXCR7 receptor antagonist is in progress and progressive multiple sclerosis will start shortly.

And a study for our CXCR3 receptor antagonist as an oral precision treatment for vitiligo will begin later in the year. Each will be a proof of concept in a specific indication under investigation as well as a proof of mechanism for a range of related disorders.

Next slide, please. We recently announced the exciting news that we have established a clear route to registration for lucerastat in Fabry disease. Fabry disease is a serious and progressive condition affecting around 16,000 people today, a number expected to rise to 21,000 by 2034. There is a high need for treatments capable of addressing disease biology across the full Fabry population as existing therapies are partially effective, have cumbersome intravenous administration or are limited to specific mutation types.

Lucerastat's mutation-independent mechanism, oral delivery and long-term data make it uniquely differentiated option in a market expected to reach USD 4 billion. The body of evidence we have generated to-date shows that long-term treatment with lucerastat consistently reduces the glycosphingolipids substrates that accumulate in Fabry disease.

We also observed a slower decline in kidney function compared with patients' prior historical trajectories. Importantly, kidney biopsy data from patients receiving long-term treatment demonstrate low to no levels of characteristic lysosomal deposits per our related data recently published at WORLD Symposium 2026.

Next slide, please. Following constructive interactions with regulatory authorities, we now have a clearly defined clinical program for lucerastat. This program builds on the substantial body of data already generated and outlines the agreed path towards future NDA in the U.S. and in line with feedback from the European Medicines Agency.

The agreed development plan includes a pivotal baseline controlled biopsy study supported by a second study designed to demonstrate that an oral therapy has the potential to deliver clinical benefits comparable to enzyme replacement therapy, which is complex and burdensome for patients.

This developmental program is structured to reinforce lucerastat's potential as the first oral monotherapy suitable for all Fabry patients regardless of mutation type. If successful, the data are expected to support regulatory submissions as early as 2029.

With that, I will hand it over to Arno to take you through the financial results and our guidance for 2026.

Next slide, please.

Thank you, Srishti. Good afternoon and good morning to everyone on the call. In my first slide, you can really see the impact of our increased QUVIVIQ sales and contract revenue, together with our cost-saving measures, resulting in a significantly improved operating result.

Net revenue of CHF 214 million includes CHF 134 million from QUVIVIQ product sales, excluding partner sales, a significant increase compared to the CHF 61 million of sales in 2024. The main driver of the sales increase is the EUCAN region, where sales increased from CHF 32 million to CHF 108 million.

The sales in the U.S. remained flat despite a significant reduction in sales and marketing costs. As mentioned by Srishti, the aim is to maintain our U.S. prescriber and patient base in a cost-efficient manner to bridge to a potential descheduling.

Non-GAAP contract revenue of CHF 72 million includes the USD 35 million exclusivity fee from the undisclosed partner for aprocitentan that was received in Q4 '24, but recognized in Q1 '25 after the exclusivity period ended without resulting in a deal.

As a reminder, the undisclosed partner was not able to close the deal for reasons absolutely unrelated to aprocitentan. In addition, we received a CHF 40 million signing and approval milestone from Simcere related to the out-licensing of QUVIVIQ in China.

The cost rationalization efforts initiated in '24 and '25 further improved our operational cost base with savings of more than CHF 80 million compared to 2024. As a result, the non-GAAP operating results improved from a loss of CHF 308 million in 2024 to a loss of CHF 100 million in 2025.

Based on successful negotiations with Viatris in Q1 '25, Idorsia's cost-sharing commitments were reduced by USD 100 million against a reduction of potential future regulatory milestones. This resulted in a gain of CHF 90 million. Other non-GAAP to GAAP differences mainly include depreciation and amortization and stock-based compensation.

This resulted in a U.S. GAAP EBIT loss of CHF 33 million. The U.S. GAAP net loss of CHF 112 million also includes the financial expenses of CHF 72 million, which also includes a CHF 61 million noncash expense related to the convertible bond restructuring and the new money facility. And we had an income tax expense of CHF 6 million.

Next slide, please. In addition to outstanding -- to an outstanding operational performance in 2025, we were also able to successfully strengthen our financial position and access to liquidity. As you know, we started the year with CHF 106 million in cash. Operational cash inflows included CHF 142 million from QUVIVIQ product sales, including sales to partners, and operational cash outflows included CHF 215 million of SG&A and CHF 93 million of R&D costs. The CHF 11 million other cash outflows mainly included working capital movements.

Further, as announced in May '25, we secured a CHF 150 million funding facility from our bondholders. And in June '25, we drew the first tranche of CHF 70 million. We also raised CHF 68 million net of cost through an equity raise in October '25 by way of an accelerated book building process as well as the sale of some of our treasury shares to bondholders.

We were very happy with the oversubscribed demand from the top-tier institutional investors that participated in the book building process. This resulted in a liquidity of CHF 89 million at the end of the year. And in addition to that, we still have access to a further CHF 80 million from the new money facility, which totals CHF 169 million liquidity available to Idorsia.

All in all, I think we can conclude that we finished the year with a strong liquidity that puts us in a good position to fund our activities going forward and leading to next inflection points.

Next slide, please. Here, we come to the comparison against the guidance. We are proud of our strong performance against an ambitious guidance target, which was significantly upgraded in May 2025. Our QUVIVIQ sales of CHF 134 million exceeded the guided sales of CHF 130 million due to an excellent execution of our commercial strategy, as Srishti already alluded to.

The company also delivered on the announced reset of the cost base. And as a result, the operating expenses, net of other income, were in line with the guidance that we provided in May '25.

The U.S. GAAP operating loss of -- or U.S. GAAP loss of CHF 33 million is lower than the guidance, mainly due to one-off lower stock-based compensation costs. Equally important compared to achieving the financial guidance for 2025 is that we've built the structures to transition this momentum into the future.

Next slide, please. We continue to guide on Idorsia net sales, excluding sales to partners because this is the performance that we can actively steer and have control over. We expect a continuous QUVIVIQ sales growth and with sales of CHF 200 million, we will have a positive commercial contribution for the first time.

Our 2026 OpEx, including cost of goods sold, will be flat compared to 2025, a little bit higher than might be anticipated in the market, but purposefully so, focused on creating shareholder value and within strategic guardrails. Our 2026 OpEx is fully consistent with a disciplined plan that supports the next wave of growth drivers. These expenditures are targeted, program-specific and clearly tied to our medium-term value creation plans, such as lucerastat program and the proof-of-concept studies with our immunology portfolio.

In a nutshell, sales are going up, OpEx remains flat and overall losses are going down, reflecting the improved underlying business performance and the embedded operational leverage within our business model.

And with that, I hand over to Srishti.

Next slide, please. Thank you, Arno. 2026 is shaping up to be a catalyst-rich year across commercial execution, strategic partnering and important scientific readouts. We are particularly looking forward to sharing the pediatric insomnia data in early Q2, along with several additional milestones throughout the year that we believe have the potential to meaningfully advance our portfolio and create value for shareholders.

Next slide. With 2 approved products with significant commercial potential and a pipeline of first and best-in-class compounds, Idorsia is positioned to create meaningful value. I am proud of the team's performance in 2025. We delivered on upgraded ambitious guidance, accelerated QUVIVIQ's commercial trajectory and continued building the foundation for long-term growth.

TRYVIO/JERAYGO represents the fourth endothelin receptor antagonist brought to approval from our pipeline, underscoring our deep expertise in this pathway and its potential in an area of high unmet need. We continue to advance other assets with discipline and focus. And as we look to 2026, we are committed to executing against even more ambitious objectives with a clear focus on delivering sustainable growth and long-term value.

With that, Nadia, please open the line for questions.

[Operator Instructions] And now we're going to take our first question. And it comes from the line of Raghuram Selvaraju from H.C. Wainwright & Co.

Firstly, I was wondering if you could elaborate a little bit further on the digital distribution model for QUVIVIQ. And specifically, a, how you anticipate this to have an impact on the forward sales trajectory; b, how it might improve your operating efficiency going forward; and c, how it could conceivably be leveraged for the use of launching additional products in the future or if it's going to be very specific to the needs of QUVIVIQ as a product franchise and wouldn't be applicable necessarily to other potential products that you bring to market in the future?

And then secondly, I was wondering if you could provide us with kind of what you see as the ideal time frame within which you would want to have a TRYVIO/JERAYGO partnership in the United States as well as regarding guidance, just some clarificatory points. Are you still confident in the previous 2027 top line guidance? Or how has that changed? And are you including in that forward assessment any potential contribution from TRYVIO/JERAYGO? Or is that going to be entirely driven by organic growth in the internal products over which you maintain commercial control?

Thank you, Ram. So the first question, area, we can tackle first on the distribution model that we're thinking about for the U.S. for QUVIVIQ. Is that the first question, area?

Yes.

And so we have -- yes, we're thinking a little bit about -- I mean, what we've learned from the weight loss space is that when there's a high degree of self-diagnosis, the ability to then find a provider and find -- be able to go into online to broaden access and broaden the availability to patients that that can have a huge unlock for certain therapeutic areas.

And we very much believe that sleep could be the next therapeutic area that could benefit from this type of model. So we've been exploring right now in the U.S. how we could do a direct-to-patient distribution model for QUVIVIQ. We've heard this is a friction right now in terms of both on the prescriber side as well as on the distribution side with pharmacies that they're not always stocking because of the DEA oversight. And so what we've understood is that some of these models for distribution can consolidate the regulations and the oversight, both on the telehealth providers as well as for the distribution. And so that's what we're exploring right now to start as a pilot in 2026.

So we definitely anticipate that this could -- in addition to our current model, be on top of that, we would anticipate that as we can get this up and running, it would have some forward momentum on our sales for QUVIVIQ. And then we would also expect that given its efficiency, we could, at some point, it would have impact as having a lower OpEx.

DTP models are common now, are getting more and more common in the United States. And so we would anticipate that if we were to make other products like TRYVIO available through that model, it might actually have an impact. But right now, the current focus really is QUVIVIQ, especially because we have more experience with QUVIVIQ and understand the points of friction that were there for patients and prescribers.

So then moving on to your second question area of TRYVIO and the ideal time frame for a partnership in the U.S. I mean with the approval and the availability of TRYVIO in the U.S., obviously our focus is to make sure that this is available to patients as soon as possible. We would actually love to scale. We know that patients are benefiting already from our focused efforts to introduce this in the top hypertension centers.

Prescribers are very eager to make sure it's available to patients. So we would absolutely love to be able to build on our very, very focused prelaunch work and scale that through partnership. And so that is top priority for the company right now is to be able to find a partner and move that forward as soon as possible.

And our efforts to do all the work that we've done on distribution with Walgreens Specialty, our work with the hypertension centers, our work on the guidelines and making sure that we're continuously present at conferences and hosting ad boards and working with KOLs is really to make this as turnkey as possible for a potential partner. So we would love to make sure that as they -- as we find that partner in the U.S. that they are able to make TRYVIO available to more and more patients.

In terms of your questions on guidance, I'll start with that, and then I'll hand it over to Arno. I think right now, the company is really focused on guiding on a one-year timeline. I think with the catalytic events and sort of the unknowns with things like descheduling, the partnership timeline, we -- it's not meaningful to guide beyond a year. And so our 2027 with outlook that we provided in May 2025, at the time it was the best available information we had. But of course, as we move forward, we are seeing more data. We see potentially we could see the descheduling, we could get more information on partnership. And so our forward-looking guidance could change in the next year. I think 2026 is actually quite a shaping year for us.

But with that, I'll hand it over to Arno to see if he has anything to add.

Yes. Maybe also to take it a bit broader because, I mean, the outlook that we gave in May 2025 was in the context of the whole financial restructuring. And I think after that, I think with the 2025 performance and the guidance for '26 and in particular, the growth of QUVIVIQ sales, we are really making clear steps to profitability and cash flow breakeven.

The 2025 sales were in line with our guidance. And our guidance for '26 is also in line with what we said in May 2025. But like Srishti said, I mean, going forward, we will limit our guidance to the current year as there are many variables and inflection points in '26 and onwards in commercial, in partnerships and also with our pipeline. And considering these moving parts, I think giving guidance beyond 2026 would not be meaningful for the market. And we would like to stay credible and transparent with guiding on numbers where we have a solid visibility.

Yes, of course. Now we are going to take the next question. And the question comes from the line of Joris Zimmermann from Octavian.

This is Joris Zimmermann from Octavian speaking. Two, if I may. First, on the QUVIVIQ pediatric data that you expect later this year in I think Q2, what is the immediate impact that you expect and kind of the next steps that would follow those data? And then also a bit from a longer term perspective, what's your strategy here? Will you pursue an updated label? Does it have -- does it come with a pediatric extension as well? So that would be on QUVIVIQ.

And then the second question on your cash and cash reach. With the current cash of around CHF 89 million and the CHF 80 million remaining from the new money facility, how would you assess your funding situation? Kind of what is the estimated cash reach? And does that include all the costs to cover the -- kind of to drive your pipeline assets and to reach all the key inflection points that you outlined in the presentation?

Joris, thank you for joining, and thank you for the questions. I'll take the first one and hand the second one over to Arno. On the pediatric QUVIVIQ daridorexant study that is -- we're expecting in Q2 2026, it's a dose-finding study. So we tested in 3 doses and we'll do a dose response curve. And so what we're expecting hopefully to see is both positive results with daridorexant in insomnia in the pediatric population as well as to get some data on the dose.

The next step would then be to take that information to the regulators and agree on a pathway forward, both with the U.S. as the FDA as well as the EMA. So we would have to run a Phase 3 program. We're expecting to be running a Phase 3 program, but we would like to shape that program based on the findings of the Phase 2. So that's where we are on the data.

I mean we're very excited, though, because there is no FDA-approved therapy for insomnia in this pediatric population. And there are no other doors with the safety profile that does non-sedative to work on the wake signal in this population. And as we know from the data that we have in the adult populations that we use all around the world, the daytime functioning could have a huge impact for pediatric patients as well. So we're very curious to see how the Phase 2 results pan out, and we're very curious to be able to shape a Phase 3 program that is able to do that later.

The other part of it for me that's very exciting is that there's the huge safety halo that comes from having a product that's effective in the pediatric population. And especially in the United States where we've had the burden of being a Schedule IV product, we would love to be able to have the safety halo that comes from showing use in the children with insomnia.

With that, I'll hand it over to Arno.

Yes. Thanks, Joris, for your question about the cash and the cash reach. I think we're very fortunate that we have a very strong liquidity at the end of the year with CHF 169 million. We clearly have sufficient cash to bring us to the next inflection points. And as already mentioned by Srishti with the previous question, I mean there are many variables and inflection points to come. So that will also clearly have an impact on our cash need going forward. But for now, I'm pretty happy with the cash runway that we have and that we're able to reach the inflection points based on which we can take additional decisions on whether to further invest or not.

Now we are going to take our next question. And the next question comes from the line of Niall Alexander from Deutsche Bank.

Hi, it's Niall Alexander from Deutsche Bank. So I guess maybe just moving to the pipeline, just on your CXCR7 antagonist in MS, I understand it's just a proof of concept right now. But it would be helpful to understand how you feel this mechanism could potentially be differentiating, and especially so to the likes of the CD20s right now or even the BTKs in the space. Just trying to understand what your hypothesis or views are on the mechanism. And then the same applies to the CCR6 and CCL20 in psoriasis. Just wondering how the mechanism there can potentially be different from the likes of IL-17s and 23s in this space.

Thank you, Niall, for the questions. Maybe I'll start with CCR6 first because that's the one that's enrolling right now. So it's a first-in-class oral small molecule, and it's selective for the CCL20-driven recruitment of the pathogenic CCR6 expressing immune cells. So we -- first thing, I think, is the potential for an oral therapy that delivers a biologic-like efficacy, and that's very compelling. We've designed the trial that evaluates the speed and the magnitude of the response as well as the dose performance and safety in the T helper 17 driven psoriasis in the PASI. And the reason we went with that test as well as with this -- with psoriasis is because that mechanism is the most clean. I think we don't see sort of off-target in that area. So we were really hoping that we could get a clean response on the PASI. So a positive outcome in this proof of concept would confirm that in the mechanistic validation and the expansion to other associated indications. And so that's kind of what we're thinking about for CCR6.

In terms of CXCR7 and the kind of the unique or the differentiating is that we have this oral, again, that is both potentially anti-inflammatory as well as remyelinating. And the brain penetrating potential is quite strong, which would have an impact in the -- to be able to transform the treatment paradigm in MS. And so the proof of concept is primarily the progression and so of the multiple sclerosis. And so what we're trying to see is if we can -- through the -- its imaging -- yes, with via imaging, we could see a slowing of the demyelination. And so that's kind of our -- the proof of concept that we've designed for the CXCR7.

Now we're going to take our next question. And the question comes from the line of Sushila Hernandez from Van Lanschot Kempen.

This is [ Sandrine ] on for Sushila. We have 2. First, could you provide more of an update on the QUVIVIQ descheduling process? Like how likely is it that it will happen this year? And second, on the Fabry disease, now that you've reached alignment with the FDA, what are the next steps? Like when will you start the kidney and the renal studies?

Thank you, Sandrine, thank you for joining. So on the first question on descheduling, we expect the next major update to be the initiation of the public comment period from the DEA. And so that's the next time we think we'll have public information available on the descheduling process.

In terms of where we are, I mean, we've now seen that -- we have probably around 13 million patients ex U.S. that have been on ADAURA across the globe between Japan, China and Europe and a couple of million patients in the U.S. And we consistently know that QUVIVIQ is valued for its safety. We don't see any meaningful signals of abuse dependence or withdrawal. And so part of our update to the FDA has been to share this kind of comprehensive ex-U.S. data.

This is on top of the Citizens Petition from '23 and a recent update that we did to the FAERS analysis. So the FAERS is the FDA's own adverse event reporting system database and where we -- again, we went back to the database and we did an updated analysis and we demonstrate that the DORA class has significantly reporting odds for adverse events related to drug abuse compared to the Z drugs and other nonscheduled drugs such as trazodone, which are used in the U.S. off-label. So we're kind of combining those things in our mind and hoping that the FDA's recommendation that moves forward is to be descheduled, but we'll only know when the DEA opens it for public comment.

That being said, I think it's important to know that we're not waiting for the descheduling to unlock the value of QUVIVIQ in the U.S. The daytime functioning in the label, the label-enhancing study as well as the work with the direct-to-patient, we're setting up those -- we're setting up the model on direct-to-patient to be able to accommodate for the current schedule as well as then expand based on any descheduling that happens.

So we are really focused on making sure that even in its current form that we can increase access for patients and they can have the benefit. And then, of course, all of those things in total, as we get more and more patients on QUVIVIQ, we can update the FDA with the safety profile and the lack of abuse signals. So that's the question, I think, probably on descheduling, but we'll only know when it goes from the DEA into public comment.

On Fabry, we're expecting to initiate the pivotal study for the biopsy in this year. And so that's the pivotal. That's the 16 patients I showed it earlier. It's baseline controlled. We're expecting to take patients that are treatment naive or pseudo-naive, and it's 18 months of treatment, and we're expecting that it's in our budget to be starting that study this year. Soon thereafter, we'll do the second study, which is to show the switch from ERT. So we'll take patients that have been on ERT therapy for a year or more, and we'll do the switch study. And so with the idea that we'd like to submit in 2029. Did I answer?

[Operator Instructions] And the question comes from the line of Myles Minter from...

Congrats on the progress. A couple on lucerastat. Just wondering if you can comment on kind of the powering assumptions for that 74-patient renal function study that you're doing against ERT in Fabry. And then I noticed at the WORLD Symposium, you seem to see a greater efficacy signal in patients with pretty severe declines in eGFR but at baseline and also antidrug antibody positive patients on the ERT side. So I'm just wondering whether you're going to stratify the readout of that trial in any way based on those factors?

And the final one is just in terms of the number of patients that remain in the open-label extension there. I think it was 47% of the original amount that crossed over. Can you just provide any sort of major reasons as to why there was discontinuations there? That would be very helpful.

Myles, thanks for joining, and thanks for the questions. I think your first question was on the power of the second study. So we were not requested by the FDA to power the eGFR study. And so that's -- so we were working under the assumption that we don't have to have statistical significance. So we designed that study with that idea.

In terms of the WORLD Symposium, the decline in the eGFR and the antibody and the stratification, I think we'll have to see where we are in terms of the eGFR study and the enrollment on how we might want to stratify that study. But right now, as we're looking for a broad monotherapy label for all adult patients with Fabry, we're not looking to kind of have a specific use in those patients with ADA. We are trying to get the label to be as broad as possible. We would like to make sure that our study design is consistent with that.

And then finally, on the open-label extension for MODIFY, that was 43 months, which was, I mean, I think, 6 years, right? Like we're in total with the 6-month MODIFY trial, that's 6 years. I mean 50% is actually a really good retention rate after 6 years. I don't know if there's anything I'm doing right now that's the same as I was doing 6 years ago. So I think that retention rate actually seems pretty good for this type of study for chronic -- for a daily oral and with for chronic condition.

And the question comes from the line of Joris Zimmermann from Octavian.

One more question from my end on the aprocitentan partnering, if I may. I was just wondering, looking at like the data is there, the data is good. The first market feedback, to my understanding, is also very positive. And now you have the whole REMS requirements omitted and you're even in the guidelines. So I was wondering what is it that is kind of -- why do the aprocitentan partnering discussions still go on? Can you maybe comment on that? So is it more on the finding the right partner in the U.S. and Europe probably? Or is it more on the deal terms? What's kind of the main discussion topic you're currently having here?

Thank you, Joris for the question. The second -- the third question, actually. So I mean, there's a lot of the positives, right? We have the data, we have the market feedback, the REMS, we have the differentiation, especially for those patients that have an eGFR down to 15 where there are no other options. And we've been in the process of looking for a partner for a while, I mean, especially even to the time when J&J decided to not pursue work in cardiovascular anymore, and we took the rights back for apro so that we could bring it forward because we have such conviction in the endothelin receptor antagonist space and its ability to be used in systemic hypertension.

Now after the approval process, I think we have gotten into a point, we're having a commercial asset that has not had the ability to be resourced for a launch. That's a new mechanism of action that is -- needs to be introduced in a pretty complex health care system right now with incredible cost pressure. And with the commercial payer system that's highly under evolution with PBMs and it's like every other week, a pharma company is being hauled into the White House. I think it's really important for partners to be able to understand the commercial fit.

And so with a commercial stage asset, the commercial fit, I think, from the partner perspective is one of the things that needs to be worked out on both sides. Like, we need to see that they're able to resource that apro or TRYVIO gets to the patients and are willing to put the effort to make sure that TRYVIO can reach the most patients, but they also need to make sure that it fits with their programs given that it's commercial stage.

A lot of the -- sort of the sweet spot for most deals is kind of a little bit before Phase 3 or at this derisking stage where they can prepare the market. And so I think right now, we're just in a peculiar stage with TRYVIO, but we are actively engaged in a range of conversations. I think one last point to make is that the sort of complicated U.S. drug pricing system and its implications for internationally are also impacting. And so that's why I think we are exploring both global as well as regional partnership. We have 2 different labels, 2 different brands, 2 doses for TRYVIO/JERAYGO, and I think that gives us the flexibility to really pursue regional opportunities. And so that's also kind of evolved our focus on the partnership discussion.

Dear speakers, please be advised there are no further questions for today. And I would now like to hand the conference over to the management team for any closing remarks.

Well, thank you, everyone, for the time today. We will have our first quarter results on April 28. And together with some of the participation that we have in investor conferences on this side of the Atlantic as well as in the U.S., we hope to get the opportunity to speak to more of you in the near future. Thank you again for joining. And with that, we can close the lines.

This concludes today's conference call. Thank you for participating. You may now all disconnect. Have a nice day.

Hi. Good morning, everyone. My name is Farhan Khan, and I'm an associate with the Healthcare Investment Banking Group here at JPMorgan. It's my great pleasure today to be introducing Idorsia. Presenting today is Idorsia's CEO, Srishti Gupta. We also have key members of the leadership team, Arno Groenewoud, CFO; and Martine Clozel, who's the Co-Founder, Chief Scientific Officer and Head of Research, will be joining for the Q&A panel.

After the presentation, we'll have about 10 minutes for the Q&A. So please hold your questions until then. And with that, please join me in welcoming Srishti.

Hi, everyone. Thank you for joining us. I'm Dr. Srishti Gupta, the CEO of Idorsia, and it is a pleasure to be here. It's the first time I'm presenting at JPMorgan since becoming the CEO in July 2025. Prior to that, I was on the Board. I've been on the Board of Idorsia since May 2021. So today, I'll share the highlights of 2025 with you as well as our strategy going forward for 2026.

So for those of you who don't know us, we built on a proven foundation; the talent, The legacy, and the drug discovery engine of Actelion. And that's the reason we have conviction in our strategy. The teams, the core science and the capabilities that created so much value in the past are the same ones that will be creating value in the future.

We are executing a focused and balanced approach to our strategy, which is to commercialize our 2 assets as well as bring our pipeline forward in a disciplined and focused way. We're committed to creating meaningful value for our patients as well as for our shareholders. Before I begin, standard disclosures, we will be making forward-looking statements.

So Idorsia is unique because we have blockbuster potential products that are commercially approved as well as a pipeline of first and best-in-class drugs. So our 2 commercial products, QUVIVIQ, which is daridorexant. It's a dual orexin receptor antagonist is poised and ready to be changing the standard of care for insomnia.

We also have TRYVIO and JERAYGO which is the first approved innovation in hypertension in close to 3 decades. It is an endothelin receptor antagonist and is approved for the control of difficult-to-control hypertension. We have commercial footprint that extends North America and Europe and we have a global footprint through partnerships with companies like Nxera and Simcere.

On the pipeline side, our track record is proven. We have 3 drugs approved in the last 4 years. We have 3 additional Phase III assets and we're in the process of starting 3 proof-of-concept trials. Multiple assets in our pipeline have multibillion-dollar peak year sales potential. We're committed to creating meaningful value for our patients through changing the standard of care and how the diseases are treated.

So I'll start by talking about our 2 products, which are entering a value acceleration phase in the commercial side.

QUVIVIQ. Insomnia, it significantly impacts both productivity and public health. We think of insomnia as a 24-hour disease because it affects every aspect of life; how you function, how you stay safe and how you work. So we see a significant impact on the productivity side with over $400 billion of global annual GDP loss because of absenteeism, which is not showing up for work because of insomnia-related sleep disorders, presenteeism, showing up and not being productive at work and overall productivity loss.

More importantly, what we see on the public health side is an increased risk of accidents and permanent work-related disability as well as sleep and fatigue contributing to long-term sleep issues in health, like -- chronic issues like cardiovascular disease, stroke, dementia and psychiatric and other related disorders.

The biggest issue that is understated in the space of insomnia is the escalating public health crisis of mis and inappropriate benzodiazepine use. This is where Idorsia comes in. we have brought forward a best-in-class asset with QUVIVIQ. It is a dual orexin receptor antagonist, and it is designed for and here for both restorative sleep and revitalized days. QUVIVIQ is the only therapy to demonstrate an improvement in daytime functioning, with statistically significant and clinically relevant patient-reported outcome that was used in the registration trial. This was the patient reported outcome that had 14 questions across 3 domains: sleepiness, alertness and cognition as well as the mood.

And we saw a significant improvement in all 3 domains with 50-milligram use of daridorexant. While the daytime functioning is included in many labels around the world, it's not included in the U.S. label. So one of our focuses this year is to do a small and focused trial to include daridorexant in the label for the U.S. And why is this important? We need to do this because we have to show that insomnia is a 24-hour disease. We also need to prove that with physicians and patients that this is a distinction thing because there's no approved products that address the 24-hour aspect of the disease. No approved insomnia product has both nighttime as well as daytime functioning.

The problem right now is that insomnia is being treated inappropriately with benzodiazepines. And part of that is the U.S. health care system, which pushes people to products that are inappropriate for use because they're cheaper, not because they're better. And benzodiazepines happen to be cheaper. They don't have a daytime functioning claim. They don't address the daytime issues. So with a claim for daytime functioning, we would be able to show that we are differentiated and can preaccess things with payers. We've been able to build QUVIVIQ into a global brand based on the fact that we've been able to address the issue of insomnia -- we've been able to address the issue of insomnia as a daytime and nighttime disease in many countries around the world because we've been able to include it in the label.

So we have shown this in Europe where we have now changed the standard of care in many countries. And our partners in Japan, Nxera have been able to show this with daridorexant as QUVIVIQ in Japan, where insomnia treatments are close to 35% of the treatment for insomnia.

In China, we're seeing that over 100,000 patients in the first few months of launch have become our -- on QUVIVIQ and we're well on our way in Europe because we see that in Europe, we have countries like France and Germany, which we have more than 5% or 7% of patients on QUVIVIQ and in France, actually, what we're seeing is that the rise in QUVIVIQ use is coming with a drop in benzodiazepines.

We're well on looking to enter partnerships in LatAm, in MENA in Israel as well as Central Europe and other countries around the world. And the fact that we are able to create QUVIVIQ into a global brand is a proof point that it's a best-in-class asset that has the ability to change the insomnia market and we're able to kind of make sure that we're able to see that the blockbuster potential is there by relaunching in the U.S. So let's talk about that.

So we have the ability to change the advanced standard of care for insomnia. We've talked about Japan, where we have over 30% use. We have Europe, which is on the rise; China, which is on the rise. So what's going on in the U.S. So we have U.S. with the idea that there's currently dissatisfied patients. We have under 2% market is in the DORA class. We have high use of trazodone inappropriately, we have high use of benzodiazepines inappropriately and we have the opportunity to completely disrupt this market.

So what is our clear path to global blockbuster potential with daridorexant. We have seen in Europe that as a best-in-class asset, we are driving up sales. And we have a path forward with 3 ideas in the U.S. As you might know, in April 2023, we filed the Citizens Petition for the descheduling of the entire class of Merck and Eisai's product as well as our product. And so what we're trying to do is make sure that we're advancing the descheduling of this asset.

In addition, we're looking at new sales models. So we've seen with the GLP-1s and other products is the direct-to-patient models. And what we're excited to do is that we're taking the same model and trying to put it forward with other assets. I think the other big thing is the daytime functioning claim.

So without any other products in this space that have the ability to affect daytime functioning, we are able to bring something forward for insomnia, doesn't -- that includes something completely distinct. So the combination of what we see in Europe, the combination of the Europe, the U.S. relaunch and as well as expanding globally, we fully believe that QUVIVIQ has blockbuster potential. And with U.S. exclusivity at least to 2036, we definitely have the pathway to get there.

One thing that I think would be completely amiss not to talk a lot about is the fact that pediatric insomnia is a complete unmet need. And this is a staggering impact both on the patients as well as on the caregivers and families. There are no approved products for insomnia in pediatric patients in either U.S. or Canada. And the approved product in Europe is melatonin and with questionable efficacy. Children with neurodevelopmental disorders are even more severely impacted by insomnia. It's more chronic, it's more severe. It affects not only the children, but also affects their caregivers.

We've estimated the prevalence to be 10% to 30% in the U.S. alone, and that's about 12 million patients right off the back. QUVIVIQ or daridorexant, and Idorsia is the only company that's actually investing in a Phase II trial for pediatric investigation. So we have a Phase II dose finding study, which is coming up in March 2026. And our trial design has included patients with not only autism spectrum disorder as well, but also patients with attention deficit disorder.

The trial is fully recruited, and we're expecting results in Q2 2026. In addition, since we're the only one who has been pursuing this as part of our regulatory commitment, this would allow us to have some patent term extension. So I can't underestimate the impact that insomnia is having in the pediatric population. And we're excited to bring forth the first and best-in-class asset as the first mover advantage to be able to treat pediatric insomnia.

Let's move on to TRYVIO and JERAYGO, the first approved anti-hypertensive therapy targeting the endothelin system. These drugs are approved in the U.S., EU, U.K., Switzerland and recently Canada.

What is uncontrolled hypertension? It's a major public health problem. We estimate 1.4 billion people around the world are living with hypertension, with 30% to 50% of them being not well controlled. In the U.S. alone, we estimate 26 million patients not adequately controlled despite being on treatment with 2 or more medications. And when uncontrolled, we know that hypertension leads to a higher risk of stroke, kidney failure, heart failure or acute -- or heart attack.

Many patients will never be controlled unless you address the underlying pathology. And that pathology is often driven by endothelin. Endothelin-mediated hypertension needs to be addressed, and we have not well -- this is the first time we have a medication that will be targeting the endothelin system for systemic hypertension.

So let's talk about TRYVIO and why it's uniquely placed in this landscape. Idorsia invested in a trial called PRECISION and it took the hardest to treat patients who had truly resistant hypertension with the broadest inclusion criteria. The study was conducted in patients after they were screened on their background therapy, and then they were put on a run-in period. And both from the background therapy and after the run-in, they were checked for their hypertension, and they were still uncontrolled. So these are truly uncontrolled hypertension patients on 3 or more medications.

The inclusion criteria included a broad range of patients, including those with congestive heart failure, diabetes, obesity and chronic kidney disease. So we had patients in chronic kidney disease with an EGFR down to as low as 15. This is actually a very unique thing if you're following late-stage assets in the hypertension space because other assets have not been evaluated down to an EGFR down to 15. So all patients were on 3, 4 or 5 or more medications at the time of screening. So this was a very rigorous trial. Now what happened after that? The FDA actually gave us a label that was broader. So it's the first dual endothelin receptor antagonist approved for systemic hypertension for patients not adequately controlled on one or another medication.

So even though we did the trial in definitional resistant hypertension, the label that was received was much broader than that. And the mechanism of action because it's unique and sort of separate from the Renin-Angiotensin-Aldosterone System allows for the safe addition to those other therapies. We've been approved, and we've been on the market. And because of that, we actually can see what the emerging clinical differentiation is. We see excellent efficacy and safety across all patient subgroups including the double-digit blood pressure reduction that we saw during the trial and even better control over the longer period of time with no increased risk of hyperkalemia, no decline in EGFR or no orthostatic hypertension. Our approach to this has been to try to take our product to some of the highest -- some of the top hypertension centers in order to understand which patients and which physicians are using it.

But let's talk about the market opportunity. We see a path to $5 billion peak year sales because there's 26 million -- at least 26 million eligible patients for the product, with 8 to 13 million of those patients not well controlled. We see readily identifiable patient population, those with CKD stage III, IV, those with obesity, elderly, the African-American population. All of these groups are likely to have endothelin-mediated hypertension.

Using some reasonable penetration and adoption principles, we see about starting off with about 0.8 million to 1.6 million accessible patients. And then with the WAC price of $775 and the strong payer support that we're seeing with reasonable utilization management criteria, we can see a path to $5 billion peak year sales. With geographic expansion in the countries of approval as well as patent life extension beyond 2034, we also see the potential with expanded indications and further evidence generation.

We have excellent feedback from the market because we're already approved. So we are utilizing some of the top hypertension centers, including Colombia, Cedar Sinai, Stanford and Duke. We see the prescriber feedback confirms the PRECISION results, and we have good tolerability and safety across patient groups. Our approach has been to start with these top hypertension centers, establish a medical evidence base and then drive adoption with other physicians.

The types of physicians prescribing TRYVIO right now in the U.S. include cardiologists, nephrologists and internal medicine doctors. Here are some of the feedback that we see from physicians. 10 to 15 mmHg drop in blood pressure, well tolerated. First time patients have an option with -- for patients with an EGFR down to 15 not having to worry about hyperkalemia, not having to worry about monitoring blood test. Resistant hypertension has its complexities, and there was a patient with a clear need, which is now normalized with TRYVIO and again, confirming the double-digit blood pressure reduction, especially in context where patients were not tolerating other medications.

In terms of the patient populations, we actually see that we have both add-on use as well as switch. So add-on, we are seeing in truly with definitional resistant hypertension. We're also seeing in those patients that are not able to take other medications, so have an EGFR down to 15, to CKD type patients. So we see a large group of patients that these physicians are using that are add-on and then we see a large group that are switch. So these are switching from medications that are not well tolerated that include spironolactone, clonidine, hydralazine and switching because of the side effect profile, the dosing or the drug-drug interactions.

So let me move on to our pipeline, which is poised to deliver the next generation of breakthrough medications. We have 2 late-stage assets in partnership with Viatris which are driving some part of our long-term value creation. Selatogrel for acute MI and cenerimod for systemic lupus and potentially lupus nephritis. As you might have heard in the Viatris presentation, selatogrel is poised and ready to change the standard of care for acute MI. It's a potent fast-acting and regulated P2Y inhibitor, which is a self-administered therapy. So upon symptoms of an MI after having an MI, we have the ability to preserve heart muscle through the self-administration of this product.

It's a Phase III event-driven study that we're doing that we -- Viatris is leading on, and they're able to enroll about over 1,000 patients a month, which is an extraordinary sort of enrollment period, and they're working very hard to make sure that their current target of 14,000 patients is met and they're able to bring this medication forward. Cenerimod is a highly selective S1P1 receptor modulator. It's developed as a novel approach for lupus. Its enrollment is ongoing with the Phase III interim results expected at the -- for the first phase is expected at the end of this year.

These are 2 assets that we are working on with Viatris that they're on the lead on that we are not making any more capital investments on, but we have a royalty and milestone payment structure that would bring value to the company on our innovation. Beyond that, we have a Phase III asset called Lucerastat, which has the potential to define -- redefine the treatment of Fabry's disease. So Fabry is estimated at a $4 billion market and it's predicted to affect 21,000 patients in key markets, which include the U.S., European 5 and Japan. It's an oral alternative to intravenous ERT. And it's non -- it's mutation independent. So we started a trial about 7 years ago called MODIFY, actually more than longer ago, to call MODIFY. It had a several -- a primary endpoint of neuropathic pain, but also its secondary endpoint of EGFR slope as well as biomarkers for urinary and plasma Gb3 levels.

Unfortunately, we weren't successful in the primary endpoint, but we had very great data from the secondary endpoint and the exploratory end points. So we decided to do an open-label extension. We've published some of the results recently in Nature Communications on the interim open-label extension, and we're looking forward to presenting full results at the WORLDSymposium for Lysosomal Diseases in February.

Again, this is a market disruptor because we can have a full mutation independent oral alternative to Fabry's Disease. And with the program that we've run with the EGFR and the kidney biopsy substudy, we have the potential for demonstrating the renal protection or the renal preservation.

We also have a pipeline of first or best-in-class drugs outside of lucerastat. we have 3 chemokines. We've mentioned those in the past. We're very lucky to have Martine Clozel here today, one of our founders and our Chief Scientific Officer. And we're happy to go through some of the mechanisms and the trial designs on those. But at a very high level, we have CCR6, which is a receptor antagonist, which we're doing a proof of concept or proof of mechanism in psoriasis; CXCR7, which is a receptor antagonist that we're using with a proof of concept in progressive MS. This compound is potentially first-in-class and best-in-class in that it has the ability potentially to both be anti-inflammatory as well as remyelinating. And then we have CXCR3, which is a receptor antagonist for vitiligo, which we will be moving forward later this year.

So we're grateful to be in a financial position to drive our growth. And for those of you who have seen us in the past, this might not have been an obvious conclusion from last year's presentation. But we now have cash runway into 2028, we have liquidity or cash and near cash assets of about USD 258 million, and our revenue outlook is around $262 million from QUVIVIQ sales in 2026. We're looking forward to providing full year guidance in the end of February.

2026 is going to be a catalyst-rich year for us. We have several areas of focus, which include continuing the sales support for QUVIVIQ as well as new distribution models. We have the global expansion that we're continuing on QUVIVIQ. We have the USD scheduling possibility in the U.S. for QUVIVIQ for the class-wide descheduling. We're looking forward to moving forward on the partnership discussions on TRYVIO and JERAYGO. We'll expand our BD efforts across our pipeline to lead where we can and partner where we should. We'll advance the lucerastat registration as well as we'll initiate the daridorexant enabling study for the daytime functioning in the label.

On the R&D milestones, we're starting CXCR7 in Q1 later in this quarter. We will report on the results from the Lucerastat study. We have the pediatric readout for daridorexant in Q2 or early part of Q2. And we also have the midyear high dose results from the C diff vaccine on our synthetic glycan program as well as the initiation of CXCR3, and again, our partner, Viatris will be reporting on cenerimod later this year.

So again, here we are with Idorsia. It's a unique opportunity for value creation because of both the blockbuster potential products, which we're moving into a value acceleration phase as well as our best-in-class assets and which we are moving forward in a very disciplined way. I joined Idorsia as the CEO from the Board to bring value to our patients, to the people at Idorsia as well as to our shareholders. And with the management team, we're doing exactly that right now. And we are trying to be as balanced and focused as we can to create shareholder value as well as set the ground for innovation going forward. And really build off the revenue that we can get with our potentially blockbuster products that are on market today. Thank you very much for your time, and I look forward to answering your questions with the management team.

Thank you so much Srishti. I really appreciate that. Great presentation. So we'll kick off the Q&A session. So if you've got any questions, please feel free to raise your hand, and we'll bring a mic to you. And please hold your questions until the mic is brought.

[indiscernible] Morgan. A couple of questions from me. One was on TRYVIO just on the -- how you're thinking about the current proportion of patients that are coming from add-on versus switch therapy, just to put that into context a little bit more? And second question is on the ASIs. I think we'll see launches from one of them at least this year. So how are you thinking about the potential impact of that on the launch trajectory for TRYVIO.

Thank you for the question. I'll take the second question first. On the ASIs, actually very grateful that the ASIs are coming into the class because they'll help us define the therapeutic area of resistant hypertension. As we are a smaller company, and we originally had this asset with J&J, who no longer is in cardiovascular, it's been really hard for us sometimes to demonstrate that resistant hypertension is truly a disease state in a disease area. There's a lot of people out there who believe that this is a compliance question and not necessarily a distinctive disease.

And as we know, there's multiple drivers that are driving hypertension, especially when patients are on other therapies and the endothelin system has been widely underrecognized as one of those drivers for hypertension. So we're looking forward to having some of the education on the resistant or difficult to control or not well controlled hypertension being set by the larger companies who are coming into the space or other partners or other companies who are coming into the space.

And then we're looking forward to differentiating ourselves being the only drug approved right now for the endothelin component of hypertension. And then in terms of the other differentiations with the ASIs, I think it's a little bit of apples and oranges. If you look at the trial designs for those drugs, the inclusion criteria as well as what type of hypertension they were treating, they were not necessarily designed to treat truly resistant hypertension.

There was a component of resistant hypertension as well as uncontrolled hypertension in their trial designs and their inclusion criteria didn't go down beyond 45 eGFR, at least in their registration trials. So we have a truly distinct value proposition and that our inclusion criteria are much broader than that. And the mechanism of action is very different.

In terms of the patients on your first question on where we see the most patients or how we're seeing the distribution of patients between add-on and switch. I think it's a little bit early for us to tell. But I think that we do see the switch patients are definitely ones that -- where the distinct value proposition is very clear because they are not -- they're not tolerating or they're not effective on the blood pressure medications they're on. And given the high concerns around polypharmacy and drug-drug interactions, we see that physicians are very excited to kind of be able to move patients off of drugs where they're not effective into a drug that's immediately almost immediately recognized as effective in them.

And then in add-on, we do see it the most first and foremost, in definitional resistant hypertension because that's where the trial is the most unique. Martine, do you have anything to add on the patient population?

On the patient population, they will be cared to take for a prescription of ASI in combination with [ AHI ] would not be probably possible. Potassium will have to be taken into account the level of kidney function at baseline where we have a very broad possibility to use without a need to control for much except pregnancy perhaps. But otherwise, there is really no need for controlling before and during treatment. There is no need for blood control, no risk of hyperkalemia, no risk of degradation of kidney function, no hyponatremia.

We're looking forward to continuing real-world evidence, though, to be able to more clearly understand what the ratios are going to be between add-on and switch. Our guidelines are open to either one of them and the label is open right now because it's on one or another medication. But as we get more and more real-world evidence with use, we're looking forward to clarifying this and then really targeting our efforts.

People who have been trying, I think, 3 medications or more and have not been, despite compliance, able to improve the blood pressure are likely to have an endothelin dependent hypertension.

I've got a question for you. Just wanted to say, obviously, congratulations on the growth and momentum of QUVIVIQ. Could you better -- could you help us better understand what is kind of unique about the design of QUVIVIQ?

Martine, maybe I'll hand that one to you to some of the properties that make QUVIVIQ the best in class.

Yes. Thank you for the question. QUVIVIQ is a result of many, many years of work to optimize the molecule to have a duration of action which would not be beyond this duration desired of sleep. So the results of the compound is that we are improving by 1 hour per night sleep duration in patients who are either having difficulties to fall asleep or patients who have waking up in the second half of the night. And the effect of QUVIVIQ on both 30-minute improvement of time to fall asleep and 30 minutes shortening of the awakening.

What is quite incredible is that because of the pharmacokinetic and pharmacodynamic properties of the molecule, which was during the totality of 7 or 8 hours of night, the morning is not associated with any carryover somnolence effect. In the contrary, we have a dose-dependent improvement in alertness in the morning. And because of this profile, we have been able to think that we could potentially improve what is one of the biggest problems of insomnia and chronic insomnia in particular, which is daytime functioning impairment.

So we developed and validated the tool, which -- it sits with PRO, where the patients are asked on 14 questions every evening. And these questions have been optimized with insomnia patients, so they are highly relevant. And we have seen attached to the profile, improved quantity and improve quality of sleep. No carryover effect. We have been able to improve this daytime functioning rapidly, but increasingly even in efficacy over time, and that's completely unique.

Thank you, Martine. Okay. I've just got 1 more question and that I wanted to bring up. You mentioned the synthetic glycan vaccine platform. So can you just share a bit more details on that.

Martine, do you want to take one?

We had been at the time of Actelion been asked to try to create a [ newco ] with another approach to the research we have been doing on small molecule organic chemistry. And we decided after reviewing many, many different technologies to create this synthetic glycan chemistry-based vaccines. And we have started working with producing a few papers on different bacterial approaches. And we have decided to go first with Clostridium difficile, which is one of the very prevalent CDC cited priorities.

And this synthetic chemistry allows to make in the lab enough of millions of doses and to be able to have a highly reproducible vaccine. But in addition to that, it doesn't require growth of the culture of the bacteria. And Clostridium difficile, for example, is an anaerobic bacteria, which is impossible to grow.

This synthetic chemistry allows to mimic a glycan, which in the Clostridium difficile situation is a natural glycan. And we have, therefore, for the very first time ever, the possibility to target not the toxin, which are easy to target, but the bacteria and the [ spores ] . And we have obtained a proof of concept, which I think is very important for the C. diff development, but also as a proof of concept for our technology beyond the Clostridium difficile. So results are showing that we have immunogenicity only after 2 injections already in a dose-dependent fashion and that is antibodies which are developed are functional, recognize the bacteria and are functional.

Behind that, we have a portfolio of vaccines, Klebsiella pneumoniae. So we are really basically targeting the [ MRAs ], the bacteria which have high likelihood of multi-bacterial resistance -- multi-antibiotic resistance. For Klebsiella vaccine, for example, so we have a lot of derivations from that research. We have the possibility to create new hybrid, for example, artificial glycans, which will cover several of the natural glycans of the surface of the bacteria. And that's what we are applying for Klebsiella. Behind that, we have Gonorrhea and we are working also on additional technologies, which are very promising.

I have one other question, which is on the SLE readout. I think you said one of the Phase IIIs might be this year. So just on the -- I think you said is a S1P mechanism, I just want to understand because there's been a lot of developments in SLE, like BAFF receptor CD40. So thinking about what we should expect to see there from you in the Phase III and why S1P might be a better target than some of the other mechanisms that are being explored.

Well, we have our partners, Viatris in the room today? But Martine, I think you were pivotal in sort of designing the Phase III program. Do you want to talk a little bit about that?

Your question was on the machanism of the Phase III readout?

Mechanism [Technical Difficulty]

Mechanism is very, very interesting. It's very broad. We are-- cenerimod is able to target basically a combination of what all other approaches are doing. And therefore, the results have been very promising for now and Viatris is now into Phase III trials in systemic lupus and lupus nephritis, I believe.

The Viatris presentation yesterday had a very thorough sort of on that one. And we appreciate that Viatris is this scale and the ability to move this one forward -- moving this innovation forward to patients. So they're right in front of you. You can grab them.

Any other questions?

Thank you for the time, everyone. We're looking forward to keeping you posted in Idorsia's progress and hopefully we will be back next year.

Thank you so much.

Good day and thank you for standing by. Welcome to Idorsia's TRYVIO Investor Q&A Webcast and Conference Call.

[Operator Instructions]

Please be advised that today's conference is being recorded. I would now like to hand the conference over to Idorsia's Chief Executive Officer, Srishti Gupta. Please go ahead.

Thank you, Nadia. Good afternoon and good morning, everyone, and welcome to our webcast to discuss TRYVIO and its role in the treatment landscape for difficult-to-control hypertension. After decades of limited progress in hypertension research, we are now entering an exciting new era, led by TRYVIO, the first innovation in hypertension in over 2 decades. It is the first and only hypertension therapy to target the endothelin pathway.

Ahead of the European Society of Cardiology, ESC, meeting, we published an on-demand investor webcast, sharing our perspectives on TRYVIO's ability to address a significant unmet need and difficult-to-control hypertension. Since then, we've engaged with leading hypertension experts at both ESC and the American Heart Association's Hypertension Scientific session. We've also met with many of you in the investor community as the back-to-school season kicks off in the U.S.

Today, we'll address the key questions we've been hearing in those discussions and then open the lines to take your questions on TRYVIO. Joining me are Martine Clozel, our Chief Scientific Officer and a recognized leader in the endothelin system; Alessandro Maresta, Global Medical Affairs Therapeutic Area Head for cardiovascular, renal and metabolism; Michael Moye, President of Idorsia's U.S. Operations; and Julien Gander, our Chief Legal and Corporate Development Officer.

Next slide, please. Before we begin the Q&A, please note that our remarks today include forward-looking statements informed by our research, physician feedback, advisory boards and market insights. As always, we encourage you to consider both risks and opportunities when evaluating Idorsia.

Next slide, please. TRYVIO in the U.S. and JERAYGO in Europe represents the first systemic hypertension treatment to target a new pathway in more than 30 years. This pathway is the endothelin pathway. That brings us to the key question investors are asking. Why is addressing the endothelin pathway such a meaningful innovation and differentiator in hypertension. Martine, can you share your perspective?

Thank you, Srishti. Endothelin upregulation is a central driver of hypertension. It plays a role at very early stages of hypertension during the progression of hypertension and at the stage of end organ damage in hypertension. But endothelin upregulation has remained unaddressed until TRYVIO. The fact that endothelin regulation was left unimposed up to TRYVIO explains why so many hypertensive patients, despite their treatment or combination of sometimes many antihypertensive drugs, could not be controlled, and their blood pressure remained higher than the target blood pressure threshold. This was particular true for certain groups of patients whose hypertension is not obviously difficult to control: African-American, elderly, postmenopausal women, obese patients, and those patients with CKD type 2 diabetes, heart failure or sleep apnea, all of which are actually associated with endothelin upregulation.

Endothelin probably also explains why the patients with difficult to control hypertension are at higher risk of death, strokes and renal failure, almost double the risk compared to well-known -- to well-controlled patients. Indeed, endothelin is a multifunctional peptide, via both its receptor, ETA and ETB, it promotes vasoconstriction, vascular and cardiac hypertrophy, fibrosis, inflammation, catecholamine release, aldosterone release and is increased by salts, thereby mediating high blood pressure, endothelial dysfunction and organ damage.

Aprocitentan blocks the actions of endothelin via both its receptors and therefore, is a multifaceted drug. In healthy volunteers with no underlying disease, even doses 50x higher than the therapeutic dose up to 600 milligrams, TRYVIO had no effect on blood pressure. TRYVIO is only active on an upregulated endothelin system like in hypertension. We proved this in Phase II and in Phase III. The lack of interference with physiology explains its very good safety and tolerability in pathology.

Thank you, Martine. That's very clear. Endothelin plays a key role, it's not been tackled until now. And by targeting the endothelin system, TRYVIO is bringing a completely novel and different approach to patients with hypertension.

Alessandro, let me turn to the PRECISION study. This was a registration trial with the design agreed upon with the FDA. Can you walk us through the key highlights from that study and what they mean for TRYVIO?

Of course, Srishti. First of all, I would like to mention that the compelling efficacy and safety of TRYVIO is well established in labeling and further reinforced by its recent inclusion in the ACC AHA hypertension guidelines. So TRYVIO achieved a meaningful reduction in blood pressure within 2 weeks. This is very important in patients with resistant hypertension that are at risk of cardiovascular events, and the blood pressure was sustained over 48 weeks with a decrease of 19 millimeters of mercury by the end of the study.

Talking about resistant hypertension, the design of the Phase III PRECISION study was especially rigorous with an 8-week running period, a standardized triple fixed dose background therapy with confirmation of compliance and inclusion of only of patients with true resistant hypertension. This trial enrolled high-risk subgroups where classical anti-hypertensive are least effective, including Black patients, all the adults, postmenopausal women, obese patients and those with chronic kidney disease, diabetes, heart failure or sleep apnea, all conditions, as you heard from Martine, associated with endothelin overactivity.

Looking at safety. TRYVIO was well tolerated with only 2 treatment-related side effects, mild early and transient edema and a modest expected decrease in hemoglobin. No direct drug interaction observed a significant advantage for patients on multiple therapies like antihypertensive patients. Importantly, no signal we've seen for hyperkalemia, hypotension, headaches nor heart rate increase. Finally, the label that the FDA approved is based on the totality of the data for adults whose blood pressure remain inadequately controlled on other antihypertensive, a broader population compared to enrolled -- in the one enrolled in PRECISION. In addition, the label includes the relevance of lowering blood pressure for reducing the fatal and nonfatal risk of cardiovascular events, especially strokes and myocardial infarction.

Alessandro, people can follow the on-demand webcast to get more details on the data for TRYVIO. But as a cardiologist, can you perhaps give us some context on the current landscape for not well-controlled hypertension?

Sure, Srishti. So today, paradigm in hypertension relies on a different classes of antihypertensive, of those addressing the renin angiotensin aldosterone system, calcium channel blockers and diuretics, which by the way, they stimulate the RAAS system. But if blood pressure remains uncontrolled, a mineralocorticoid receptor antagonist such as spironolactone can be added, but many patients do not tolerate it, mainly due to hyperkalemia, worsening of renal function, gynecomastia and in addition, we observed a high discontinuation rate.

So despite all the classes of antihypertensive drugs, millions of patients remain uncontrolled and TRYVIO offer a solution with a completely new mode of action.

Thank you, Alessandro. That certainly highlights the significant unmet need that a safe and effective drugs like TRYVIO can address in the current landscape. What about compounds in development?

Yes, Srishti, there are several products in development, but most of them are still targeting the RAAS system, including the aldosterone synthase inhibitors. These drugs are still in development, and we don't know yet what their label will look like. But what we know is that the studies were not as robust as PRECISION in enrolling true resistant hypertension patients. And there are safety concerns such as hyperkalemia, hyponatremia and decrease in renal function, particularly if combined with other drugs that are targeting the RAAS system. And this is where TRYVIO stands apart. It addressed the endothelin pathway, a fundamental driver of disease, that other treatments don't reach with a proven efficacy and a good safety and tolerability profile.

So TRYVIO is differentiated to the current and potential emerging treatments. Which patient populations do you see TRYVIO being used for?

So if we take into consideration the new mode of action, the efficacy and safety profile and the FDA granted label, TRYVIO is the ideal choice for many patient groups. I can list for you some: patients with risk factors for hypertension, which will be difficult to treat because they are endothelin-dependent; black, elderly obese patient, patients with sleep apnea, type 2 diabetes, early heart failure and chronic kidney disease. Then we have patients that are not adequately controlled despite 2 lines of hypertensive therapies and patients who cannot tolerate certain classes of drugs because of their side effects.

There are also the patients that we have studied so they're truly resistant hypertensive patients that are not controlled despite treatment with 3 or more therapies at their maximum tolerated dose. And then I would like to tease out the patients with chronic kidney disease stage III and IV and resistant hypertension because for these patients that have currently no alternatives. In all these patients, TRYVIO represented an obvious choice with very little competition.

Thank you, Alessandro. So there's a large addressable population of patients with hypertension that is not adequately controlled. Michael, given that the U.S. market is essential to realizing TRYVIO's full potential, can you walk us through the key drivers that support our $5 billion peak sales estimates?

Yes. Thanks, Srishti. Our forecasts are grounded in extensive market research and analytics to understand both the size of the opportunity and how physicians intend to use TRYVIO.

Next slide, please. So today, of the 40 million treated patients in the U.S., there are roughly 26 million patients treated with 2 or more therapies. And 30% to 50% of those are inadequately controlled despite receiving treatment and therefore, eligible for TRYVIO according to the FDA label with the only contraindication being pregnancy and sensitivity to aprocitentan. This population is expected to grow, given the aging demographics, higher rates of comorbidities linked to endothelin function and increasing recognition of the severe consequences of uncontrolled hypertension.

Importantly, these consequences are already reflected in the FDA indication that removes any need for a separate outcome study. We estimate that around 7 million patients as we move to the middle of the slide -- the 7 million patients are easily identifiable and are well defined a good area to focus on first coming into the market. Patients with endothelin-driven comorbidities often face restrictions with other therapies. Chronic kidney disease, as you've heard, is a prime example -- it's a prime example. Patients with hypertension and CKD are often treated with 2 or more agents yet few effective options exist.

TRYVIO is approved for patients with an eGFR as low as 15 and has demonstrated excellent safety and tolerability with no hyperkalemia and no hypotension. Other identifiable groups include patients who can't tolerate certain classes of drugs and those with true resistant hypertension. So we now have real-world efficacy and safety outcoming the mirror of what we saw in PRECISION.

These drive adoption and penetration assumptions. So as you can see, they range here from 12% to 22%. So our insights are informed by over 1,000 qualitative and quantitative interactions with multi-specialty physicians, including top hypertension centers. Physicians consistently recognized TRYVIO's efficacy, safety and its unique mechanism of action when they're addressing -- that address what additional RAAS blockade cannot. In comparison with emerging therapies, TRYVIO is viewed favorably by these physicians, particularly for patients with CKD and based on the impact on both blood pressure and uACR measures.

And finally, the payers, which we know are all very important, have responded very positively, highlighting the robust primary endpoint of more than 15-millimeter drop from baseline, the statistical strength and the sustained efficacy through the duration of the PRECISION study as very compelling reasons for coverage. We have set a WACC at $775 a month and we're focused on a very favorable gross to net as a first-in-class differentiated therapy. TRYVIO is currently being reimbursed with reasonable utilization management criteria, which supports our commercial model. Srishti?

Thank you, Michael. Beyond the U.S., we also see an additional upside from geographic expansion. Aprocitentan has already improved at JERAYGO in the EU and the U.K., and there is significant opportunity in Japan and China. We also see that we can get further value through IP extension strategies, for example, with fixed-dose combinations with the SGLT2 inhibitors and indication expansion such as exploring renal protective benefits in CKD. Of course, realizing the full potential of TRYVIO will depend on securing the right partner, which is why we're actively engaged in these discussions at this time.

Julien, could you share a little bit more about how we're thinking about partnering discussions?

Yes, happy to. Look, we've been very consistent in saying that we lead where we demonstrate scientific or commercial advantage and strategically partner where external expertise, scale or speed adds value. So specifically on TRYVIO, partnering TRYVIO remains a key strategic priority for us. We are actively engaged in discussions with potential partners, which reflects the interest in the assets and the opportunity TRYVIO represents. While this process takes time, we're encouraged by the progress and look forward to updating you as we move forward.

In the meantime, I can tell you, we continue to work very diligently and at high speed to maximize the value of TRYVIO. We've seen some of this in the past weeks and months. I think of the REMS removal, the collection of early, very positive real-world experience, the inclusion of TRYVIO in the ACC AHA hypertension guideline. And very recently, the recent initiative announced with Duke and Stanford University.

Thank you, Julien. Having addressed some of the key questions that we have received around TRYVIO, I think it's a good time to open the lines for additional questions. Nadia, can you please go to the next slide and open the line, please?

[Operator Instructions]

And we're going to take our first question. It comes from the line of Joris Zimmermann from Octavian.

This is Joris Zimmermann from Octavian. I have two questions. One will be on partnering that you just highlighted, Julien. Is there any timelines you could give us? Or at least do you still expect to close a deal this year? And then the second question would be until you have found the right partner and signed an agreement, and given the limited resources you can currently deploy in the U.S., where will you put your focus in terms of the aprocitentan launch.

Thank you, Joris. Julien, will you respond to the questions?

Yes, very happy to. Thank you, Joris. Look, I mean you will understand that we cannot really comment on specific timelines. But what I can say, and I can ensure that the partnering aprocitentan is really a key priority for us. And to your point, we resource this project accordingly. We, of course, want to move very quickly and also considering the time advantage we have towards emerging therapies. But you will understand that actually, our focus is not only just speed, but it's also securing the right partners to maximize TRYVIO commercial success.

To your second point, Idorsia is indeed has limited capacities, but I think considering these constraints, we've done a lot to make sure that the product is advancing, is prepared to be launched. And the product is commercially available, and we have very good early evidence, and we'll continue those efforts, and we are hoping to give you an update as soon as we can on achieving this goal of partnering.

Thank you, Julien. Michael, maybe I'll have you add to that with your presence at the AHA -- recent AHA meeting and some of the other work that we're doing on retail distribution.

Yes. Thanks, Srishti, and thanks for the question. Yes, we -- despite these -- the resource constraints, we are quite busy continuing our kind of launch and market prep. So Srishti, as you said, we're at the major congresses. So we have a really strong presence there. We're working with a lot of the top KOLs and a lot of the top hypertension centers. You heard about the Duke, Stanford relationship that come out. We are -- have really finalized a lot of the core materials. So we have a full digital presence. Our consumer and HCP websites are up and running. We've got print materials and things out there.

And then the last couple of things. We're continuing our payer discussions, which continue to go really well. And then as Srishti made reference to at the end, the pharmacy distribution. So once the REMS was removed, we're able to move in addition to having a specialty pharmacy, we are quite literally right now coming online with full retail distribution across all retail pharmacies in the U.S. So yes, despite the resources, we're making great progress, again, across KOLs, congresses, payer discussions and pharmacy distribution. Srishti?

Thank you, Michael. Nadia, we'll take the next question.

[Operator Instructions]

We have a follow-up question from Joris Zimmermann from Octavian.

Okay. Sorry. I hope I didn't jump the line now. But two more questions. I mean you talked about the patient populations and that you see a very broad target population. But maybe you can give us an idea based on this broader label that you got versus the study inclusion criteria, what are the kind of -- where do you see the quickest uptake in the market? Which type of patients do you think will be the ones that physicians consider prescribing aprocitentan first? And then also, maybe you could give us a little bit an idea of the hurdles that you foresee as well.

Joris, thank you for the question. Michael, would you like to walk a little bit through how we think about the targeting of the patient populations in the U.S. and how we might access them with the centers of excellence.

Yes. So when we look at that and we look at both our research and our interaction with the physicians, we're definitely seeing the data across all the subgroups has been one of the things that's jumped out of physicians. So you heard a little bit in our opening that clearly, the CKD is a differentiated piece and that we see that as a great opportunity. The other thing about the subgroups that we're seeing kind of across these multiple comorbid patients, you heard about patients challenge with hypertension management, black patients, obese patients, again, patients with CKD.

The thing about the profile that continues to jump out is the fact that we don't -- we have efficacy and safety across all these subgroups. We don't have any real exclusions or contraindications and especially we don't have any drug-drug interaction problems, obviously, with these patients being on multiple medications.

So when we think about those different subgroups and those comorbid patients that are at more risk, including the CKD patients, we see consistently the one pill, one dose, once daily, good tolerability, no drug interactions. That allows -- those factors are what the physicians are pointing out to us that allow us to treat these high comorbid risk subgroups.

Thank you, Michael. And Joris, in terms of your second question, I'd like to turn it over to Alessandro. Alessandro has been attending a lot of the KOL meetings in all over the United States over the last couple of months, meeting physicians, understanding how they think about TRYVIO. So Alessandro, can you talk a little bit about how you think about the hurdles that physicians are thinking about as they are deciding on prescribing TRYVIO.

Thank you very much, Srishti. I think that, in my opinion, the best -- the most important hurdle is the new mode of action. The physicians are used to the RAAS system, are used to calcium channel blockers and now they need to realize and understand that there is a new kill of the block that is an endothelin receptor antagonist, and that endothelin receptor antagonist can be very, very beneficial in the subgroup of patients that I and Michael highlighted.

So basically, I see this as the major hurdles because the results are really impressive. The safety profile is also very, very good. And we have a clear understanding on which are the patients that would benefit the most from this -- from TRYVIO. And last but not least, there are many, many patients that despite they add on 2, 3 or even 4 drugs, they are still not at goals. And these patients, they need -- they deserve treatment. So I don't see many hurdles in front of us.

Alessandro, thank you for that. And it underscores the importance for us of finding a partner who can help us on the broad outreach and the medical education required to enhance the importance of the end -- addressing the endothelin upregulation that occurs in a lot of hypertension. So this is definitely something we are thinking about and focused on as we move forward. Joris, thank you for the questions again.

Thank you. Dear speakers, there are no further questions for today. I would now like to hand the conference over to your speaker, Srishti Gupta, for any closing remarks.

Thank you, Nadia. So this concludes today's call. Thank you for joining us and for your continued interest in Idorsia. Our next scheduled update will be on October 30 when we report our third quarter results and will provide a comprehensive update on QUVIVIQ performance. Operator, you may close the line.

This concludes today's conference call. Thank you for participating. You may now all disconnect. Have a nice day.

Good day and thank you for standing by. Welcome to the Idorsia Half Year 2025 Financial Results Webcast and Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to our first speaker today, Andrew Jones, Head of Corporate Communications. Please go ahead.

Thank you, Nadia. Good afternoon and good morning, everyone, and welcome to our webcast to discuss the financial results for the first half of 2025. Presenting on the call today, we have our new CEO, Srishti Gupta, who will share her impressions of her first weeks in the new position and the company's revised strategic priorities. Also presenting, we have Arno Groenewoud, our Chief Financial Officer. Then, joining us for the Q&A session, we have a big selection of management. We've got Julien Gander in his new role of Chief Legal and Corporate Development Officer; our President of the EUCAN region, Benjamin Limal; our President of the U.S., Michael Moye; and Chief Scientific Officer and newly appointed Head of Research, Martine Clozel; and Alberto Gimona, our Global Head of Clinical Development and Medical Affairs.

Next slide. Before handing over, I need to remind everyone that we will be making forward-looking statements. You have, therefore, been warned appropriately about the risks and opportunities of investing in Idorsia. And with that, I will hand over to our new CEO, Srishti Gupta. Next slide.

Good morning, good afternoon, everyone. Thank you for joining the call today. It is an absolute pleasure to be presenting to you today as the CEO of Idorsia. Here is a bit of background for those of you who I have not yet met. I joined the Board of Idorsia in 2021, most recently serving as the Chair of the Nominating, Governance and Compensation Committee. So I'm very familiar with the company, its portfolio of products and pipeline assets, and the excellent passionate team working here. Though I've only been in the role for about a month, being on the Board helped me quickly get a sense of where we are and where we need to go. I've been focused on setting clear strategic priorities with the teams and I'm excited to share those with you today. Next slide, please.

Before we jump into those, I wanted to reflect on where we are now compared to where we were a year ago. From a performance perspective, Idorsia-led QUVIVIQ net sales in the first half of 2025 more than doubled compared to last year, rising from CHF 23 million to CHF 56 million. This demonstrates strong commercial traction and growing demand. It is driven by Europe and Canada and a stabilization of an optimized model in the U.S. We also see an improvement in our non-GAAP operating results. from negative CHF 170 million to negative CHF 15 million. Arno will share our financials in more detail later on.

I commend the team on the strong performance. The results confirm the commercial acceleration of QUVIVIQ, coupled with the financial discipline implemented over the past 12 months have successfully delivered on an operational turnaround. A few other highlights to share, QUVIVIQ is a truly global brand with rapidly growing sales. Most recently we worked with our partner, Simcere, for approval and the national reimbursement drug listing in China. I will share more on TRYVIO later on, but I can already tell you that the removal of the REMS by the FDA and the positive real-world experience collected so far highlights the significant commercial opportunity. We are making focused investments in advancing our pipeline, which I will also share today. Notably in the first half, we have seen new data with lucerastat, which supports further Phase III investigation in Fabry disease and the first results with our synthetic glycan vaccine. We have secured additional financial stability with the extension of our cash runway to the end of 2026, and this puts us on track to commercial profitability in 2026 and overall profitability in 2027. Next slide, please.

In my first 4 weeks in the role, I had the chance to meet with teams across the organization. I also had the opportunity to conduct an initial review of commercial plans and portfolio programs. I wanted to lay out an early view of the strategic priorities for the company, which we will continue to refine in the coming months. First, we must unlock the full value of QUVIVIQ, as this medicine is unique and can drive significant value for patients around the world. It is also a key driver of our profitability. Second, expanding our strategic partnership will be critical to advance both our commercial and our pipeline objectives. Third, at our core, we are a science-based company that has a deep pipeline across many major unmet needs. Accelerating these high-value medicines is a top priority for our R&D organization. Fourth, we need to continue balancing our commercial and pipeline ambitions with strong financial discipline. And finally, we need an inspired and engaged organization to reach our full potential for our patients and our shareholders. Next slide, please.

Let's start with unlocking the full value of QUVIVIQ. We have demonstrated that QUVIVIQ is the driver of growth for our business. To realize the full potential of QUVIVIQ, we will accelerate commercial momentum by expanding reach to patients, optimize our market presence globally, and continue to generate evidence supporting medical utility. Next slide, please.

QUVIVIQ is not a best-in-class dual orexin receptor antagonist, or DORA, by accident. It is the result of the team designing a dual antagonist with the goal of a rapid onset of effect and a duration of action sufficient to cover the night, but short enough to avoid any negative next morning residual activity. There is a large market opportunity for the treatment of insomnia disorder and DORAs have made limited inroads in many markets, so there is significant growth potential. We have, however, seen DORAs make significant growth in other markets, such as in Japan, where they constitute around 30% of the insomnia market. So there is potential for this to change. The expanding demand and accelerating sales from commercial execution is putting us on the path to profitability with multiple upside opportunities, for example, the descheduling of the DORA class in the U.S., which I will touch upon later. We are receiving extremely positive feedback from both health care professionals and patients who confirm the excellent sleep efficacy, the improvement of next-day functioning, and an excellent safety and tolerability profile. Next slide, please.

We are excited that QUVIVIQ's global footprint is expanding. Idorsia commercializes QUVIVIQ in North America and Europe. It is available in Japan through our partner, Nxera, and it will soon be available in China. We have worked with our partner, Simcere, to establish the regulatory pathway for approval in China and leverage the wealth of data we generated in our global program. Simcere did an outstanding job of rapidly advancing this to approval so that QUVIVIQ will be available to patients. I think it will actually be available to patients as soon as the end of August. We're also discussing distribution agreements in Latin America and the Middle East and North Africa, and I look forward to updating you on those in the near future. Next slide, please.

So now for the headline news. I'm excited to share how QUVIVIQ is poised to fundamentally reshape the insomnia treatment landscape in Europe. In the first half of 2025, 25 million restorative nights and revitalized days have been prescribed in Europe. QUVIVIQ is the only pharmacological treatment for long-term management of insomnia disorder, improving both nighttime sleep and daytime functioning, with an established safety profile designed for chronic use. Our approach in Europe is to address access upfront, and we have secured public reimbursement in the U.K., France, Germany, and in Austria, which recently happened on June 1. Our top priority is securing public reimbursement in additional markets as this is how value is unlocked and scale achieved. Alongside access, we invest in focused promotional efforts targeting psychiatrists, neurologists, and sleep specialists to better -- to build trust in our clinical evidence. And finally, we continue to expand into primary care with copromotion partnerships, such as with Menarini in France and in Germany, as well as omnichannel initiatives to reach general practitioners. We look for partners who have established presence and relationships with the GP prescribers. By doing these 3 things well, we will grow QUVIVIQ's reach and position it as a key contributor to our commercial profitability goal in 2026. Next slide, please.

Since the launch in the U.S., over 620,000 QUVIVIQ prescriptions have been dispensed, and the product has been prescribed by more than 56,000 health care professionals. At the beginning of 2025, the company implemented a streamlined, focused, and more cost-efficient commercialization approach for QUVIVIQ to maintain its availability and sales until the potential descheduling of the DORA class. Syneos Health is executing a highly-targeted digital marketing plan supporting 20 virtual sales reps. While sales remain relatively flat with a slight decline, we're seeing a very meaningful improvement in gross margin, driven by a greater proportion of payer-paid scripts. We continue to advocate for descheduling of the DORA class, and we believe that the FDA review of the abuse potential of the DORA class, also known as the 8-Factor Analysis, is actively moving forward. We are hoping to hear the results of their analysis and the next steps from the FDA and the DEA soon. Next slide, please.

Let's turn now to the growing data showing how daridorexant is delivering meaningful value in clinical practice. We are very excited to be advancing the recruitment of our Phase II dose-finding study in pediatric insomnia. The initiation of this program is driven by 2 critical observations: one is the undeniable unmet medical need for pediatric populations as there are no currently approved medications in the U.S. and only a subset of patients in the EU are eligible for medications in insomnia; and two, the profile of daridorexant positions it as an ideal candidate to address this treatment gap. The study is expected to complete enrollment by the end of 2025 with a readout expected around mid-2026.

Physicians often see patients with insomnia who also face challenging comorbid conditions, such as anxiety, depression, obstructive sleep apnea, nocturia, and menopausal symptoms. While the insomnia of all these patients can already be treated with QUVIVIQ on label, we are supporting ongoing research to build a robust evidence base for the treatment in these medically complex populations. Real-world observation studies are demonstrating effectiveness of QUVIVIQ in patients with psychiatric comorbidities, such as anxiety or depression, supporting its use even in polypharmacy settings. We are also supporting the creation of an evidence base for the use of QUVIVIQ in insomnia with concomitant substance abuse disorders, and these studies underscore our commitment to furthering the science of sleep and insomnia. Next slide, please.

Moving to expanding strategic partnerships. Our goal is to both strengthen current alliances and actively pursue new high-impact partnerships. These allow us to scale access and commercialization, to accelerate development, and to enhance long-term value creations. Next slide, please.

We collaborate with partners who share our belief that science can transform lives. Partnerships take many forms: copromotion partners expanding QUVIVIQ's reach to general practitioners like our partnership with Menarini; distribution partners opening new markets; and co-development partners enabling approvals in specific geographies like our recent success in China with Simcere. We aim to secure new partners across these models to bring QUVIVIQ to more patients around the world. We also pursue partnerships to accelerate R&D like our collaboration with Viatris. We have licensed 2 Phase III products to Viatris, selatogrel and cenerimod. This is a great example of how we've partnered with a company committed to building an innovation-based portfolio and capable of advancing large-scale clinical studies while allowing us to retain value of our discovery efforts. Viatris is executing well on recruitment. And if all goes to plan, we look forward to data readouts next year. Next slide, please.

Partnering aprocitentan remains a top priority, and we are actively engaging in partnership discussions. As a reminder, aprocitentan is approved under the trade name TRYVIO, in the U.S. and JERAYGO in the EU and U.K. It is the first and only endothelin receptor antagonist approved for the $12-plus billion uncontrolled and resistant hypertension market. And until the approval of TRYVIO, the last new drug class for hypertension was over 30 years ago. It is estimated that 50% of adults in the U.S. live with hypertension and 50% of those patients are not well controlled despite being on medication. TRYVIO, therefore, meets a significant unmet need. The FDA has granted an indication that includes patients on one or more antihypertensive drug, a less restrictive [ drug ] criteria than we set for ourselves for the PRECISION pivotal study, making the addressable patient population significantly larger. The label for TRYVIO reflects both its double-digit blood pressure lowering effect and the clinical outcomes benefit linked to that reduction, as you see on the slides. That label was improved in March 2025 when the FDA removed the REMS requirement, making it easier to prescribe and to distribute. Its efficacy and safety profile, particularly in patient populations with difficult comorbidities, differentiates it to existing therapies and any of those in development.

Specifically, TRYVIO offers clinical differentiation in patients with comorbid hypertension and chronic kidney disease, as patients with hypertension and renal impairment have significantly fewer treatment options due to contraindications and safety concerns. TRYVIO can be prescribed to patients with an eGFR as low as 15 milliliters per minute with no risk of hyperkalemia. TRYVIO has an excellent safety profile with low discontinuation rate observed over 40 weeks, no drug-drug interactions, hypotension, or hyperkalemia, again, seen on the adverse reaction table from the label as shown on the slide. Prescribers and KOLs, many of whom are at hypertension centers of excellence, confirm interest and the need for a new mechanism of action, especially in patients whose hypertension is difficult to treat and those patients who have chronic kidney disease.

Finally, early feedback from payers is that they are receptive and are working to establish reasonable utilization management criteria to ensure patients will have access. TRYVIO is ready to launch to the millions of patients who could benefit from this outstanding drug, and I look forward to keeping you updated on the efforts to find a partner who has the capabilities and the capital to maximize its impact. Next slide, please.

We recently shared positive news on the Phase I study, which included safety and immunogenicity for our C. diff vaccine. As a reminder, C. difficile is the most common cause of health care-associated infections in the United States and the leading cause of hospital-acquired diarrhea. It is responsible for approximately 0.5 million infections and close to 30,000 deaths annually, along with significant morbidity from recurring infection and complications like colitis and sepsis. Vaccine development in this space has proven difficult due to C. diff's complex biology. because of the hard-to-eliminate spores and the toxins that impair the body's immune response. Our vaccine candidate targets the bacteria and the spores. It also importantly validates the approach of using synthetic glycan antigen technology to target a range of complex pathogens that have been resistant to more traditional vaccine approaches. We are looking for a partner to realize the full potential of our synthetic glycan approach. Next slide, please.

Turning to our pipeline. We are focused now on advancing our highest value assets in a disciplined and an efficient manner. Next slide, please.

We are advancing 4 investigational clinical assets with the potential to transform treatment paradigms. Lucerastat is our oral substrate reduction therapy with the potential for organ protection in all adult patients with Fabry disease. End organ protection remains an unmet need and is essential in Fabry's disease because it helps delay or prevent the irreversible damage that ultimately drives disability and early mortality. The results of both interim analysis of the open-label Phase III extension study, where patients have been treated for at least 42 months, and a kidney biopsy substudy are supportive of further investigation for patients with Fabry disease. And we are in continued discussion with the U.S. FDA to agree on the optimal regulatory pathway to approval.

As I mentioned earlier, we are doing a dose-finding Phase II study with daridorexant in pediatric populations. And during the full year 2024 webcast, we also shared that we will advance 3 first-in-class chemokine receptor antagonists into Phase II. Each will be a proof-of-concept in the specific indication under investigation, as well as a proof-of-mechanism for a range of related disorders. These include CXCR7 for remyelination in progressive multiple sclerosis, CXCR3 for precision treatment of vitiligo, and CCR6 for T helper 17-driven psoriasis and related autoimmune disorders. We will provide more details on these programs as these studies progress. Next slide, please.

Turning our focus to financial discipline. Our goal is to balance ambition with accountability. We will stay laser-focused on smart resource allocation, growth-oriented cost discipline, and value-driven decisions. And with that, let me hand it over to Arno. Next slide, please.

Thank you, Srishti. Good afternoon, good morning to everyone following on the call. Let's start by looking at the operating results. Here, you can really see the huge impact of our cost-saving measures together with the greater commercial contribution and higher contract revenue. Net revenue of CHF 130 million includes CHF 58 million from total QUVIVIQ product sales, a significant increase compared to the CHF 24 million in the first half of 2024.

The main driver of the sales increase is the EUCAN region, where sales increased from CHF 9 million to CHF 44 million. The sales in the U.S. remained relatively flat despite a significant reduction in sales and marketing costs. As already mentioned by Srishti, the aim is to maintain our U.S. prescriber and patient base in a cost-efficient manner to bridge to potential descheduling of the drug. Contract revenues of CHF 72 million also includes USD 35 million exclusivity fee from the undisclosed partner for aprocitentan that was received in Q4 '24, but recognized in Q1 '25 after the exclusivity period ended without resulting in a deal.

As we already mentioned before, the undisclosed partner was not able to close the deal for reasons absolutely unrelated to aprocitentan. In addition to the exclusivity fee, we also recognized a CHF 40 million signing and approval milestone from Simcere related to the out-licensing of QUVIVIQ for the Chinese market that will be received in Q3 2025. The cost rationalization efforts initiated in Q4 '24 further improved our operational cost base with savings of close to CHF 50 million compared to the first half of 2024. We will continue to balance necessary investment in QUVIVIQ expansion and our R&D pipeline with the objective of reaching overall profitability starting from the end of 2027. As a result, the non-GAAP operating results improved from a loss of CHF 170 million for the first half of 2024 to a loss of CHF 15 million for the first half of 2025. Next slide, please.

Let's now look at the bridge from non-GAAP operating results to U.S. GAAP net income. Based on the successful negotiations with Viatris in Q1 2025, Idorsia's cost-sharing commitments were reduced by USD 100 million against the reduction of future regulatory milestones. This resulted in a gain of CHF 90 million. Other non-GAAP to GAAP differences of about CHF 10 million mainly include depreciation and amortization and stock-based compensation. Together, this resulted in a U.S. GAAP operating profit of CHF 64 million. The U.S. GAAP net income of CHF 52 million includes also the financial expenses of CHF 8 million and an income tax expense of CHF 4 million. Next slide, please.

We started the year with CHF 106 million in cash. Operational cash inflows included the CHF 58 million from QUVIVIQ product sales and the operational cash outflows included CHF 101 million of SG&A and CHF 46 million of R&D costs. The CHF 15 million other cash outflows mainly include working capital movements. Further, as announced in May '25, we secured CHF 150 million funding through a new money facility from bondholders. In June '25, we drew the first tranche of CHF 70 million. This resulted in the liquidity of CHF 72 million at the end of June 2025. Note that this liquidity does not include yet the CHF 40 million milestone from Simcere, which we expect to receive in Q3. And there's also an undrawn amount of CHF 80 million under the new money facility. So if you would consider also these items, the cash runway now goes out to the end of 2026. Next slide, please.

The guidance for the Idorsia-led business remained unchanged from the improved guidance that we published in May this year, with expected sales of CHF 130 million and a non-GAAP EBIT loss of CHF 175 million. We've updated the guidance for the partner-led business due to the higher milestone payments from Simcere, which result in an overall non-GAAP EBIT loss of CHF 100 million and a U.S. GAAP EBIT loss of CHF 55 million. This guidance puts us on track to reach commercial profitability in 2026 and overall profitability as for the end of 2027.

And with that, I hand back to Srishti.

Next slide, please. Thank you, Arno. Finally, we continue to focus on building an organization with a strong culture. Our ambition is to invest in a high-performance organization grounded in clarity, collaboration, and ownership. We want to enable teams to move with speed, adapt with agility, and deliver meaningful results. Next slide, please.

Our science makes a difference because of the people behind it, their expertise, dedication and drive to turn innovation into impact. We combine deep R&D capabilities with seasoned commercial teams who ensure that our medicines reach the patients who need them. I'm consistently struck by the talent and commitment of our people. They are our greatest asset, united by a shared purpose and focused on delivering long-term value for patients, partners, and shareholders. Next slide, please. I don't have this slide.

I want to thank the Idorsia Executive Committee and their teams for the progress we have made over the past half year, and also take a moment to highlight some recent changes. Martine has served as the Chief Scientific Officer since the start of Idorsia. Under Martine's scientific leadership, Idorsia's discovery engine has produced one of the richest pipelines in biotech, grounded in rigorous science and a deep understanding of unmet medical need. As she now also takes on the role of Head of Research, she will bring renewed focus to advancing our most promising early-stage assets. In addition, Julien, our Legal Officer, has also -- our Chief Legal Officer, will also lead corporate development to support strategy, strengthen internal governance, and promote partnerships and alliances by overseeing our business development efforts. As we live the principle of leading where we can and partnering where we should, partnerships and alliances would be an important source of revenue as we find ways to accelerate development and as pathways to reach more patients around the world. Next slide, please.

In conclusion, the first half of 2025 reflects delivering sales guidance for QUVIVIQ and well-executed financial discipline, putting us on the path to commercial profitability in 2026 and overall profitability starting from the end of 2027. Moving forward, we will work with urgency to deliver on the 5 strategic priorities we have laid out today. I look forward to providing updates on our progress in the quarters to come. Thank you so much for your time, and I will hand it back to Andrew.

Thank you, both. And now we have time to take your questions. As I mentioned at the beginning, we're also joined by Julien, Benjamin, Michael, Martine and Alberto. With that, operator, please, could you open the line for questions?

[Operator Instructions] And now we're going to take our first question, and it comes from the line of Sushila Hernandez from Van Lanschot Kempen.

I have a few, if I may. To start off, could you help us understand what the difference is between commercial profitability and overall profitability and what is needed to fill in the gap? And then I have a few more follow-up questions.

Thank you, Sushila. Maybe I'll hand over to Arno to take us through that.

Sure. So commercial profitability means net sales and commercial OpEx. So that should be positive in 2026 for the full year. And overall company profitability also includes the R&D expenditure and SG&A. Does that answer your question?

Yes, sure. And could you walk us through how the descheduling process works? What could be the outcome of the update that we're expecting soon?

Thanks, Sushila. Michael, would you take that and take us through the process as we understand it?

Yes, sure, Andrew, and thanks, Sushila, for the question. The process of descheduling is ongoing. The next steps we expect to hear from the FDA is them sharing their scientific opinion with the DEA. We hope this will happen soon. And this would be a significant milestone and a positive sign to the market. At this point, the DEA would then post their scientific opinion for public comment and evaluation for the decision. So the kind of underlying important piece of this is how does this all develop? And that is based on the adverse event profiles related to the abuse potential of the DORA class. So the FDA looks at their adverse event database called FAERS. It is much less than that seen for other -- the DORA class, much less seen for widely used insomnia products in the U.S., notably zolpidem and even trazodone, which we know is not even indicated for insomnia. So the analysis that the FDA has done out of their own database confirms the safety profile of the DORA class and in particular, [indiscernible] direction. So as Srishti said earlier, we really are hoping and have a strong feeling that, that analysis is progressing, and we hope to hear from the FDA very soon.

And Sushila just wanted to add that in addition to the FDA's analysis, Idorsia has also reviewed the adverse event profile related to the abuse by looking through the FAERS database, the FDA adverse event database. And we noticed that it's very much less than the other widely used insomnia products, including zolpidem and trazodone. So we've done independent analysis. So we remain hopeful that the analysis will be consistent with the FDA's analysis. So we haven't just left this to the FDA to do an independent analysis. We have been looking at this since 2023 when we first filed the citizen's petition for the descheduling of the DORA class. And it's our understanding that the Eisai and Merck have also continued to monitor both their adverse events and think about the descheduling of the class as well. So we are fairly confident that in totality, the evidence base exists that we will be able to achieve the descheduling of the class. I think it's just a matter of the process playing itself out.

Okay. That's clear. And then just maybe I missed that also in terms of time line. So we're awaiting this analysis. So once this analysis is in, what are the time lines that we can think of in terms of the DORA class being actually descheduled?

It's not 100% transparent in terms of the process, but what we understand is that there is an FDA clearance process where the analysis moves its way through the FDA and then it is then submitted to the DEA. The DEA then puts it up for public comment, in case there's public commentary on the view of the descheduling and that can be positive where people are supportive of the descheduling of the class. And then upon that, the DEA makes the final recommendation. So while we know that there is a time line of an estimated 8 to 10 weeks in terms of the FDA clearance process, we don't have visibility on the time line that the DEA puts out for public comment and for their final decision.

Based on the analogs that we've looked at for other descheduled products, we think that after the submission to the DEA, we're probably on a time line of around 6 to 9 months. But of course, I think that it's important to note, Sushila, that the government looks very different in the United States now than it did under any of those other analogs. So I think we're trying to remain agile and flexible around that. And actually, Michael and I will be in Washington, D.C. in early September, and we look forward to providing an update in Q3 on what we learned from our time with HHS.

Maybe to add to that, also the descheduling of QUVIVIQ in the U.S. is an upside in our model. So...

It s not included in guidance.

It s not included in the guidance.

1

Okay. That's clear. And then for aprocitentan, so the REMS are removed. What else are you doing to make this product more attractive? What market preparations are you currently conducting? And what are you looking for in a partner?

Thank you for the question. We're very excited actually right now. There's quite a drumbeat around resistant and uncontrolled hypertension from some of the other products in development. And I think the thing that we're most trying to emphasize, in addition to the REMS removal, is that this product is already approved. So there is actually no uncertainty as to what the label will say. There's no uncertainty as to what payers will say. Payers are actually giving us the positive feedback that there will be utilization management that is consistent with being on one or more therapies, which is what is in the label. So we are just trying to communicate with sharp messaging that without the REMS, this is a product that has easy distribution and prescription without monitoring. We're communicating what our real-world experience is with prescribers who are -- where the product is available by medical exception in the United States right now. And one of those -- the things that's being highlighted in its current use is the potential in patients with chronic kidney disease without having to monitor for hyperkalemia because of the eGFR levels going down to 15. So we think that there's differentiation to products that are currently available and anything in development because of this -- our CKD data. And even before a deal, I think what we're hoping for is that our data on CKD will actually be published in scientific literature and that the U.S. Hypertension Guidelines will be updated, I think, in the next few weeks, and we're hoping the mention of the novel class of the new drug class for the treatment of systemic hypertension will be recognized by the AHA's Hypertension Guidelines.

[Operator Instructions] Dear speakers, there are no questions over the phones at this moment.

Okay. Thank you, Nadia. In that case, maybe I can put a question to you based on the request that we see coming through the Investor Relations mailbox recently. Srishti, I think everyone can see that you've gotten up to speed in record time. On this basis, what catalysts are you most excited about over the next 6 to 12 months?

Thank you for the question, Andrew. So over the next 6 to 12, maybe a little bit longer, 15 months, I think, let's talk about a few key things. This one may seem obvious, but I think we need to continue to deliver on our ambitious QUVIVIQ sales target quarter after quarter. And this is for us to just keep on track to achieve our commercial profitability and our overall profitability. In Europe, this means continuing to secure access and reimbursement in the public markets, as well as expanding to the primary care partnerships that we discussed. And then, as Arno mentioned, capturing any potential upsides that we would have from the descheduling of the class. And then I think, as we also mentioned, we're really looking to make sure that this product is available to patients worldwide. And we think that there's large unmet needs in markets like Latin America, the Middle East, and North Africa. So I think if we can stay on target for QUVIVIQ quarter after quarter, that will actually be a big catalyst for us.

Again, we talked about apro. I think that's another significant opportunity for us to both enhance the value of the company's science and sort of recognized science that we have out there, as well as start to pay back some of our debt that's sitting in the special purpose vehicle. We expect to, as I mentioned, to publish some data in CKD, as well as see the updated guidelines coming out of the U.S. And then we also talked about the regulatory milestones that we're hoping for coming out of our pipeline. So the FDA, we're hoping to have an agreed-upon path forward for the Phase III registration work for lucerastat. We hope to initiate the Phase II proof-of-concept studies for our 3 chemokines over the next 6 to 12 months. And we are continuing our Phase I program of our vaccine platform, and we're hoping to have identified a partner to help us take that one forward.

And finally, we're very excited about our partnership with Viatris, which holds the assets selatogrel and cenerimod and recruitment into those Phase III studies are ongoing. So over the next 6 to 12 months, I think, we're also hoping to see some of the readouts from that work, which actually could continue to contribute additional upside for Idorsia shareholders.

Great. Thanks, Srishti. Nadia, do we have anybody who's joined into the queue?

Not at this moment. [Operator Instructions]

Okay. If we're not seeing any other questions coming in, I think I understand it's summer holidays for many people, including quite a few of the people joining the call today on our side. So thank you very much to our team for doing that. I would say, in that case, if anybody comes up with questions afterwards, we're always on standby to help you. And then we'll conclude the call for today. We have third quarter results coming out on October 30. And you'll see that the management team will be traveling more in the next few months. So hopefully, we'll get an opportunity to meet with more of you in the near future.

With that, Nadia, please close down the lines.

Thank you, everyone.

This concludes today's conference call. Thank you for participating. You may now all disconnect. Have a nice day.