Study Update

Mar 10, 2021

Press Release

Good afternoon, everyone. This is Andrew Weiss, Head of Investor Relations and Corporate Communications here at Hydorsio. I welcome you to today's call to discuss the 2nd set of Phase 3 results for daridorexant in insomnia. In the call with me today are our CEO, Jean Paul Clozell and our Global Head of Clinical Development, Guy Brownstein. Both are here to walk you through our presentation and prepared remarks, which will then be followed up with a Q and A session. In that session, Martin Clozell We'll be able to also take questions. Next slide, please. I do need to remind everybody that we will be making forward looking statements. Therefore, you have been properly warned about the risks and opportunities of being invested in Hydorsia. Next slide please. So hence I have the pleasure to hand over the call now to Guy. Please take over. Thank you, Andrew, and good morning, good afternoon, everybody. This is a presentation of the 2nd pivotal study of daridorexant and it's a follow-up discussion. I want to remind you that the first study results were shown in April 2 months ago, a bit more than 2 months ago, and I want you to I want to refer you also to the presentation that we delivered at that time. Of course as we now have the 2 studies, it will be interesting to look at the data side by side, which will be done in the course of this presentation, which is leading me to the main conclusion that we draw from the second study that we now have 2 positive finger trials of daridorexantininsomnia and also the remarkable consistency of the results between the two studies. Next slide please. We must be now on Slide 4. So this is a summary slide of the overall program that we have. We completed a while back a Phase 2 program with 2 Phase 2 studies, 1 in adults and 1 in elderly subjects. That was important because we could define those levels that we wanted to study in the Phase III program. And it was also interesting to note from this Phase II program that the same dose could be administered to adults and elderly patients. As a consequence, we could set up 2 pivotal studies looking at 3 different dose levels. The first study, called 301 that we reported in April, looked at the dose of 25 milligrams and 50 milligrams and the second study that we are going to describe today looks at the dose of 10 25 milligrams of daridorexant. In both studies, we included adults and elderly subjects. The studies at a 3 month duration and included patients with moderate and severe insomnia. The efficacy parameters, safety parameters were identical between the two studies. We had objective and subjective split parameters collected by Polysomnography. I described them in details in the previous presentation, and I would like again to refer you to that presentation for details, and we can discuss that in the Q and A if you need. But I also want to mention that we had a range of subjective endpoints assessing the night using what we call the LDQ, the Sleep Diary Questionnaire, which allows the patient to report on their feeling about their night and in particular the total fleet time that they perceive they have set. We also had, and that's unique to this program, an assessment by the patient themselves of the data and functioning using an instrument that is called the ITC, insomnia daytime symptom and impact questionnaire. This is a questionnaire that we developed at Hydorsia and validated according to the FDA guidance. And again, I will refer you to the previous presentation for details and we can discuss this instrument during the Q and A. As mentioned, we have now replication of the 2 confirmatory studies. The safety assessment included, of course, adverse events and a number of other parameters like vital signs, biochemistry and dermatology. But more important and more specific to Insomnia products, we also collected using a specific tool that I will come back on later on, the next morning residual effect. And we also collected the withdrawal and physical dependence and rebound of insomnia after withdrawal of the drug during a 1 week observation. In addition to this program, of course, we have a clinical pharmacology program, which is not totally completed, and we will report later on this program in a separate call. The next slide, Slide 5, is showing the design of the trial, which you may remember is identical to the Phase 3,301 study that we reported earlier on. Just to remind you, there was a screening period of up to a month. The second part of the screening period was actually a single line placebo run-in phase. And during that placebo in Phase. We collected subjective assessment using the sleep diary questionnaire, assessment of sleep as well as polysomnography, which is represented at visit 3 by the 2 bubbles. So we collected the polysomnographic criteria over 2 nights, consecutive nights, allowing a clear assessment of the baseline. Following this placebo run-in phase, the patients were then randomized at VIVID 4 into 3 groups placebo, 10 milligrams 25 milligrams of darithorexant. This was given to patients for 3 months and we had at 1 month another 3 months assessment of polytomnography again through 2 consecutive nights. During this whole treatment period, we continue to collect daily assessment of sleep as well as the daytime functioning using the Eatsheet questionnaire that I mentioned before. After the 3 months when the patient had completed 3 months, they enter then into a single blind placebo run out trial of 1 week, which we continue to collect data assessment of sleep as well as the data and functioning and we also included 1 placebo night to look at withdrawal symptoms and rebound during this period. Finally at the end of the single blind placebo pair, the other patient entered into an extension study if they want further. The next slide is showing the study objectives. The primary objective was to evaluate the efficacy of 25 milligrams and 10 milligrams of daridorexant on Objective C parameters collected by the polysomnography in patients with moderate and severe insomnia. The secondary objective was to evaluate efficacy of 25 10 milligram daridirectional and subjective sleep parameters collected with the LDQ, the sleep diary questionnaire, as well as the data and functioning collected with the Aeti questionnaire in patients with moderate ancillary insomnia. The 3rd objective. The safety objective was of course very important to assess safety and tolerability of the hyalorexant, not only during the treatment phase, but also upon treatment discontinuation to look at rebounds and withdrawals. On the next slide, Slide 7, we have now the description of the primary and secondary endpoints and how they were analyzed. 2 primary endpoints were defined. These were nighttime primary endpoints looking at the Weighting After Sleep Onset by Polystonography, we call that WASSO and also the Latency to Persistent Sleep, LPS, yes also collected by polysomnography. We have 2 secondary endpoints, one dealing with the night aspect, which the subjective total sleep time recorded with the SleepDairy questionnaire. And we have the sleepiness score of the ITC questionnaire, which is assessing how patients function during the day. These subjective endpoints, subjective sleep time and the sleepiness score were recorded every day on average over the treatment period on every week. The endpoint was the last week just preceding the Police Endography Nights. We analyze these endpoints according to the 10 milligram versus placebo dose as well as the 25 milligram versus placebo, and reanalyze these endpoints at month 1 month 3. If you make the calculation, you will realize that here we have 16 comparisons versus placebo. And of course we wanted to have a study wise TAK1 error control at 0.05. And this is important in the context of making labeling claims. There has been a lot of questions when I presented that slide 2 months ago, similar slide for the 301 study. There has been a lot of questions about the structure of these 16 comparisons and so far we were quiet about it, but it's probably time now to disclose and discuss more fully how this was organized. This is shown on the next slide, Slide 8, which depict graphically how we organized the 16 comparisons. So I will try to explain that in as simple terms as I can. You see here the 16H hypothesis comparison H1, 2, 3, 4, 5, 6, 7, 8 on the left and then 9, 10, 11, 12, 13, 14, 15 and SCENE. The H1 and H2 were VASO comparisons and LPS comparison, respectively. The green a diagram shows the high dose versus placebo. For that particular study, this was 25 milligrams versus placebo at month 1. The blue following the green shows a high dose comparison 25 milligram versus placebo at month 3. And then moving on to the right side of the slide. We have this pink showing the low dose 10 milligram of specified MOS-one and the purple part which shows the low dose 10 milligram of pacibat MUN-three. So essentially what we did was to prioritize 25 milligrams above 10 milligrams and then within a certain dose level to prioritize month 1 to month 3. And therefore the order of comparison was high dose month 1, followed by high dose month 3, followed by low dose month 1, followed by low dose month 3. And within each of these buckets, high dose month 1 or high dose month 3, low dose month 1, low dose month 3, then we organize the comparison of the primary and secondary endpoints in a certain way. We started with Wazone LPS, followed by H3 STST, the subjective total sleep time, followed by the ITSA questionnaire, H4 and similarly H5, 6, 7, 8 for the low dose for the high dose placebo at month 3 and then again H9, 10, 11, 12 for the low dose per specie by month 1, H13, 14, 15 16 for the low dose perspecibalkon3. What I would like to point out as well is that we started with the alpha value type 1 error of 0.05. And we carry on this alpha level according to how the statistical response is to the hypothesis. So initially, we divided alpha into 2 and give identical weight to Wellstone and LPS. So therefore, the H1 and H2 are tested statistically at 50% of the alpha, starting with 0.05, we divide into 2. So H1 and H2 are tested at 0.025. If we can reject the hypothesis 1, then we can carry on the alpha level to the next level down. And to do that, we divided the alpha level that is remaining. So for example, if you win on H1, we can carry on 0.025, we don't lose any alpha and we carry on to H5 and H3 similarly. So therefore, we divide the alpha of 4.025 into 2 identical levels, $0.0125 that goes to H3 and similarly the same amount goes to H5. If we also win on H2, we proceed in the same way, carry on half of the alpha remaining, which is 0.025, half of it going to H3 and half of it going to H6. By doing that, if we win on LPS and Wazo, the alpha of is received from VAZO and LPS and therefore receiving half of each, we again have a full alpha at that level. In contrast, assuming that we fail on H2, we don't reject H2 LPS as an example, then we lose the alpha that goes together with this comparison. So the alpha of 0.025, which was associated with H2, is lost. However, as you see from the network of arrows, we can still continue to do the analysis. The H3 can still be tested because half of the alpha from H1 is retained and then H3 can be tested at half of the alpha that was given to H1. If we win on H3 this time, we can also continue to H4, But interestingly, we can also continue to H6. Even if we lose, for example, our H2 LPS at month 1, we can still go to H6 and test the LP attached 3 months. So this is the methodology we have used to TEST 16 hypothesis. This has been fully discussed with the FDA and agreed by the FDA. The last remark I would like to provide, which is important for this call as well, is that we don't need to win on more than 1 of the 2 H1 and H2 2 to claim significance because they are tested independently. We are not in a situation of co primary endpoints where you have to win on both of them to claim positive study. Here by dividing the alpha from the very beginning, we can claim positive if H1 is rejected or if H2 is rejected. And this is important in the context of the current discussion. This is what allows me also to claim that the 302 study that we discussed today is a positive trial. I hope that was clear. It's a bit technical and complicated, but because I've received questions on many occasions about this control of TYK1 error across the 16 comparisons. I wanted to give you a bit more clarity on how it was done. So the next slide, Slide 9, is now showing very classically the study patient disposition. As you see that we had to a large number of patients, more than 3,600, nearly 3,700 to get 9.20 for randomized, 25% of the patients who have randomized, 75% didn't pass the criteria that we set forth in terms of randomization. This was primarily due to the fact that the patient recorded not sufficient insomnia on the subjective Dari questionnaire and also for the polysomnographic criteria. We wanted to be sure that we had very clear criteria for moderate and severe insomnia and therefore a number of patients had milder disease and therefore couldn't be randomized. So now continuing from the randomization, what we see, which is really very nice, is that we have a very high completion rate, 93%, very few patients dropped out. And then the follow-up was the placebo run out. Also, we have nearly complete data on the withdrawal during the run out, withdrawal of treatment and then nearly half of the patients that were randomized we could continue into the binding extension. The binding extension, which we call the 303 study, it's still ongoing and I'm not in a position to report the data from that study now, but this will be the purpose of follow-up conversations. I'm sure you would like to see the results of the study and that will be shown on the next slide, Slide 10. First, I would like to describe how the slide is constructed. On the left, you see the results of the first pivotal study similar to what we presented at the previous teleconference. On the right, you see the results of the new study. On the left, you see the results in green of the 25 milligram as placebo. And as a reminder, we see that there was significant improvement on both LPS and Wazuh at month 1 as well as LPS and Wazuh at month 3. And you remember as well that the 25 milligram versus placebo was significantly improved for LPS and Wazuh, the study was positive on these two endpoints, as well as a 3 month for LPS and Wazo. This is known and you have seen that before. The new study provides very similar results. The 25 milligram of placebo shows numerical improvement of LPS, which was of borderline significant, the same at 1 month 3 months. And for our well thought, it was highly significant at 1 month 3 months. Interestingly, the 10 milligram dose placebo showed miracle improvement on all these parameters actually not reaching statistical significance. And when we look at the numbers, which I'm not allowed to give you because we would like to preserve the scientific integrity of publications, I can tell you that the 25 milligram was numerically always superior to the 10 milligrams. So we see an effect at 1 month. It was sustained at 3 months and there is high level of consistency. You may question why we don't have numerical improvement, but no statistical improvement of our EPS. I can't give you again the numbers, but I can tell you that numerically they are actually very close the 25 milligram data that we had in the first study. The next slide is showing Slide 11 is showing the results for the subjective TST. And as we see here, on the left, we have the positive data for 50 milligram versus placebo at months 1 month 3 for subjective total sleep time and similarly for 25 milligrams as placebo. In the new study, the 302 study, we see on 25 milligram daspasibo significant improvement at 1 month and at 3 months on STST. And again, for the 10 milligram asplacibole, there was numerical improvement of a lower magnitude compared to 25, the structure of the alpha spending function, so that you understand that even if we don't reject the hypothesis for LPS, we could still test the subjective total sleep time, although it was a secondary endpoint. So again, the effect that we observed at 1 month was sustained at 3 months. The next slide, Slide 11, will show the results of the dial time functioning using the ITC questionnaire and the sleepiness domain. Guy, you're on Slide 12. Just you said 11, sorry. Yes. Slide 12. Thank you, Andrew, to remind me that. On Slide 12, we see the 866 lupine domain. This is an assessment of the patient data and functioning. The results were significant for the 50 milligram of placebo at 1 month 3 months and numerically better than placebo at 1 month and 3 months for 25 milligrams, we have very similar results in the second study with numerical improvement the zucatibon 25 milligrams, actually larger than 10 milligrams and not reaching statistical significance. So again, we see the consistency of the studies the effect that we had sustained from 1 month to 3 months. So this is, in a nutshell, the results of the efficacy data that we collected during these two studies. I will now move to the safety data, Slide 13, and this is an overview of the treatment emergent adverse events. We see that there was no huge difference between Okay. Again, showing the first study on the left and the second study on the right, we see that the number of adverse events, we don't see much the difference between placebo and the active doses of daridorexant. We see no tendency to dose response between the the different doses. We see very, very few patients that had adverse events leading to premature discontinuation. We see very, very few harmful number of serious adverse events and also a very small number of adverse events of special interest, which were adverse events adjudicated blindly by an independent adjudication committee. Slide protein. The next slide is showing a bit more details on the type of adverse events. We see high level of similarity between the two studies, the main adverse event being mesopharyngitis, which I believe is really innocent. We see a few patients with headache. We see very little number of patients with fatigue, dizziness, somnolence, you see the data here, accidental overdose and NOSEA. So no surprise of these numbers and they are very aligned to what we observed in the 301 study with again no tendency to an increased number of events from 10 milligrams to 25 and then to 50 milligrams. On the next one, Slide 15, we give you a bit more data maybe that you haven't seen so far, events adjudicated by the Safety Committee and you see the numbers here. It's very difficult to debate about these numbers because they are very, very small and for some like narcolepsy like symptoms related to complex sleep behavior including hallucination, sleep paralysis. You see a very small number, but I cannot give you the breakdown by treatment group because this would have the potential to unblind the 303 study because these patients are actually continuing in the 303 study and therefore knowing which treatment group they are would potentially unblind the study and the three zero three extension is blinded. And then on the bottom, you see again the repetition of the somnolence, same number as before, and the number of adverse events, which are very relevant to an insomnia product, in particular, the number of fall that we had. You remember the small number in the 301 study, we have also a very small number in 303 and also depressed mood, again, very small number of patients. So overall, we are very pleased with the safety results. I can now move on to Slide 16, which is my concluding slide using the same format as we have used in the previous presentation. The tick box indicates that we could reject hypothesis and demonstrate efficacy on Wazdan LPS at 50 milligrams 25 milligrams in the first study and for Wazol in the second study being close to significant for LPS in the second study and nothing significant for the 10 milligrams, which is actually something we find very interesting. From a safety perspective, we didn't see those dependent treatment emergent adverse events. We see very low rates of clinically relevant adverse events. And I can add that we didn't see morning handover effect. This was assessed using a visual analog scale every morning as part of the SDQ questionnaire, assessing whether the patient would feel some unknowns resulting from the a drug that was given the previous night and we see rather a tendency to an improvement versus baseline an improvement on active as placebo. And we didn't see any sign of rebound and we didn't see any sign of withdrawal symptoms during the placebo run out period. Having said that, this completes my presentation, and I will hand over to Jean Paulain. Thank you, Guy, and again, congratulations for this program. Maybe I can go to the next slide. And just to say, Hydorsia took a lot of risk in designing this program because in contrast to what is done usually, we tested 3 doses in Phase III. We really wanted to web statistical analysis, including 16 comparison, 4 main primary endpoints with 2 time points, 1 month 3 months. And also, we had planned a design where the middle dose 25 milligram would be common to the 2 studies and the data would be in a later possibility in a better time could be good. And I think that this program really shows the fantastic results because the two studies are very consistent as was mentioned by Guy. And now with this data, I think clearly we have a very good idea of the dose response. But usually in Phase III, you get you never get such precision not only on the dose response for efficacy, but also for safety, because we have seen that 10 milligram has nearly no effect, but 50 milligram has outstanding effect without safety penalty. And this information I think is key for the authorities, for the regulatory authorities and this is the reason why now we are really working and the whole company is working very hard to submit an NDA before the end or around the end of this year, and we are going to meet the FDA this autumn to prepare for this filing. So that's the very important point. Now we have to prepare for the launch. So what next slide. So we are on Slide 18. So what is going to be important for a successful launch. First of all, of course, we have very clear data. And and when you will see the data, you will understand how, I would say, tracking how 2 studies can give data so close. And more important, I would say, than even the data is the drug, because we have a very unique drug. And again, I would like to say, it's not by chance that we have seen this outstanding effect. It took us the project started 22 years ago, and it took us this is the 3rd drug that we put in clinic. We wanted to have absolutely a drug with a very fast onset of action, peak effect around the big dose in the pharmacokinetic of 1 hour and we wanted a shorter start around 5 to 6 hours to allow for getting an effect on 3 point sales, while without having this morning hangover effect. And of course, there is still the finding about the data. I mean, these are outstanding findings. We still do not know what is the mechanism of this improvement of data and functioning. And of course, it's going to be very interesting to go through the data and to try to understand better these findings, which is really striking. As we said, this NDA will be fine before the end of the year. And now the company has to get prepared for the commercial launch. And you will hear more during this year, but we are working very hard in terms of branding, but also in terms of preparing, especially the United States affiliate in order to be able to launch in the best condition, very direct sense. Next slide. Slide 19. So I think that what is important is that this program has to be put into the context of our vision in Hydorsia. Clearly, it shows our ability to innovate Because we were the first of the team who have discovered, David Oraxane was the first to really go in clinic with a product blocking orexin receptor. This was Amorexant at this time. So we are really in the middle of innovation. But as I have mentioned, what was also very important is not only to have the right concept, but to have the right drug. And it Lucas, I think, more than 25,000 drugs to be synthesized in order to discover direct science, which is absolutely unique in terms of pharmacokinetics and also pharmacodynamic properties. But then as you have seen, what is also very important in Hydorsia is a patient focused drug development. And this focus on really trying to understand better what is legal for the patient, what is his main issue, why does he suffer? It's quite unique. We did that with sponazimod for fatigue. We are doing that with Gary Dorexant for the daytime performance. We are going to do that with decelerat for pain and this pain question. So I think it's one characteristic is that we not only go to the simple or I would say usual endpoints, but we try to really evaluate what is important for the patients. And finally, even if we are now just starting with the group of Simon Jones, this building of this commercial organization. I think we understand very well what is needed for commercial success. And I can tell you, we do not even if we have very good products, very good products, a very good product and a very good product, we do not believe that it's going to be selling by itself and we are getting prepared for very large efforts for this commercial launch because we will need to work very hard to really get the full potential and full commercial potential of this product. I think that now if I remember you and I like consistently also not only within two studies, but also with what we say. This is the first slide and this is our strategy. As it was explained to the investors who have decided to come with us 3 years ago when the company was created. We are on Slide 20, right? Sorry. Slide 20, sorry. So we wanted to clearly expand what our strategic priorities. So number 1 was and it's really giving us a 5 year the scale. First one was to really bring 3 products to the market. And Constell, I really think that with the regulator, we will have the first one. We are now working very hard for the other projects, but they are moving so well. So that's in a good way, this book. Number 2 was clearly to create a commercial organization. This is also underway. And as I mentioned, and we wanted to bring hydorsia to profitability. And I think that with a drug such as daridorexant, it will give us a very good tool to grow our sales and hopefully to reach profitability in a reasonable amount of time. We also wanted to create a pipeline with sales potential a peak of €5,000,000,000 or more. And I think that with the overall pipeline, we are also on a good way to have the drugs which will allow to reach its goal. And finally, we want to use a state of the art technology. This is and you cannot see that, but this is now true with artificial intelligence that we are integrating into drug discovery. This is true, as I mentioned, into the new ways we are evaluating clinical we are making clinical programs. This is we're going to be true with our launch, which is going to use a lot of digital technology. So I think we are within that time, there is a return. We are on a good track and the Hydorsia is really in a very good event, a much better position than ever. Thank you. That's my next slide. Thank you, Jean Paul. Next slide, please. So now we're in the position to be able to take your questions. For this part of the call, Martine will be able to join us. Please remember that this is a presentation on Phase 3 data. So keep your questions to the topic. Questions on commercialization or on financial numbers, who will be able to address at a later time. Operator, please open the lines. Thank you. Ladies and gentlemen, we will now begin our question and answer session. The question we received is from Rajan Sharma of Deutsche Bank. Your line is now open. Please go ahead. Hi, Anne. Thanks for the question. I'm just hoping you could help us understand the somnolence rates between the 25 milligram and 50 milligram doses. Obviously, in the first trial, there's a higher rate associated with 25 milligrams versus 50 milligrams, and that seems to be consistent here. So just kind of To get your thoughts on any reason for this would be really helpful. And then secondly, just to clarify, do you expect to get the data from the long term safety study, so Study 303 prior to the FDA meeting. Thank you, Rajan. So Guy, can you take those questions on somnolence rates 50 milligrams 25 milligrams your expectations for the 303 data. Yes, starting with the 303, yes, we the data to be available prior to the interaction with the FDA. That's not important from an efficacy perspective, But it's important from a safety perspective because as part of this 3 0 3 study, we have sufficient amount of patients treated for up to a year. And of course, as we are looking for a chronic indication, we need this data. So that will be available. The second question is about insomnia sorry, somnolence and the lack of dose response. I think it's an interesting observation. It's very, very difficult to comment on very low number. The message for me is more that we have very low level of somnolence across all those levels. It's probably in keeping with the pharmacokinetic of the product and the fact that the half life is reasonably short, ideal for an insomnia product and therefore the patient would not feel stimulant during the day and not report somnolence as an adverse event very frequently. So we see very few. And what is also very interesting for us is to see that there is certainly no more patients with standard launch at 50 milligram that's at 25 or 10. And therefore, I think having now shown that 10 milligram doesn't provide much benefit and 50 milligram providing more benefit, it gives us a good chance to maybe achieve the right dose in our labeling. Thank you, Guy. Next question, please. The next question we received is from Craig Schwabian of Goldman Sachs. Your line is now open. Please go ahead. Hey, good afternoon, good morning and thanks for taking my questions. I was curious And I might have missed it, my apologies. But did you look at next day performance? I know that was one of the key attributes that you highlighted Study 301 and just wondering if it was measured what you saw in next day performance. So that would be my first question. And then my second question really has to do around what doses just to confirm what doses you do plan on filing and do you expect to get differential claims for both doses or do you expect what's the thought on kind of what you think the label is going to look like? Thanks. Thank you, Greg. So Guy, I think both questions are for you, the one on next day performance as well as our filing thoughts. Yes. On the first question first, before answering the question, I would like to be sure that we talk about the same thing, which is daytime performance. There is a bit of semantic here, of course. I do not want to be too complicated, but There is also the issue of next morning residual effect versus daytime functioning. So I believe what you are talking about either daytime functioning using the ITC questionnaire that we have developed and validated. And The question was about the effect that we observed, right? Yes, I mean can you describe without giving the numbers, is there an effect, how is it affected? Yes, this questionnaire is made of 3 domains, and I would refer you to the previous presentation where this is described, a presentation that is still on our website. One domain is the sleepiness domain, which has a number of questions within that I also described on the slide that I presented last time. And this is the one that we use as secondary endpoints. And we demonstrated that on 50 milligrams, there is a very highly significant effect on this domain. We have not disclosed the numbers, but I can tell you that we as part of the development of the questionnaire, we also validate what would be clinically perceived by the patient, what would be clinically relevant. And on this domain. We can claim that the effect we observe is clinically important for patients. We have not reported on other domains, but I can also reassure you that there is consistency of the other domains. One was called the alert commission domain, the other one was the mood domain. And of course, there is this overall questionnaire. And without disclosing the data, I can tell you that it's very consistent across the 3 domains and the total score on 50 milligrams. Now turning to 25 milligrams. What we observe is a numerical effect, which is not too distant from the 50 milligrams that it's in between placebo and 50 as you would expect. In the second study, we have actually very, very similar results of the 25 milligram on this questionnaire. So there is total consistency of the 25 milligram effect on the daytime performance. As I didn't mention before, but it's in our press release, we are going to complete the analysis of this program by combining the treatment groups that we can combine for the 2 studies through a pooled analysis, and these are the 25 milligram groups and the placebo groups. And I'm very confident that by putting the 2 studies together on the different endpoints, we will have extremely good and precise estimates of the effect of the 25 milligram dose, including on this daytime performance. Now turning to the second question, I would be speculating on what we are going to decide in the next weeks And I can do that. What is most difficult is to speculate on what the FDA will tell us because I'm not part of them, but certainly our intention is to take advantage of the lack of efficacy demonstrated of a very small efficacy, I would say, of 10 milligrams, the good efficacy of 25 on the very good efficacy on 50. Saying that, it's giving maybe a bit of light on our idea of trying to put out in our submission to go with 25 50 milligrams. But of course, this will also depend on the interaction we we have with the FDA later in the year and how they reacted to our data. And the final those that will be labeled will be known once we have the drug approved. Okay. Thank you. If I could just have a follow-up. So I believe Davego is approved in 5 10 milligram and Belsomra is approved At 5 to 20. So do you have a perspective at this point in time given the data that you've seen about how Dorito, Rexant compares across the 2 other approved dura products in terms of efficacy? Yes. This is, of course, a question that we are, of course, debating and looking. I would maybe tell you 2 things. 1 is versus Lumbrexant, which is the most recently approved. If you look at the labeling, the data presented in such a way that it's very, very difficult to know exactly in terms of minutes by how much the treatment effect is, and this makes the comparison very, very difficult. Having said that, we can have estimates and certainly on the Knight assessment, we are not inferior at all. But what the second part of my answer is that what we have in our program is actually unique because not only we could see an effect which I believe is at least as good as during the night, as good as what is seen with lumbarixant and suvorexant. We are adding a new dimension in our database, which is the daytime assessment. Nobody has ever developed an instrument that is as comprehensive as the one we have. Nobody has done during drug development assessment of the daytime performance to the level we did it using validated tool daily measures and we are in a unique situation now to be able to differentiate the product not just on the night, but also adding a new dimension with the data and assessment. And we do that without impacting the safety of the patient. So I think your question is about the differentiation. Here, we primarily differentiate the product by the information we have on daytime performance and the safety is very good, which is also in relation to the pharmacokinetic profile of our product and especially you would see the data you have seen the data you can compare in respect to Cermelo's and Tectepl, for example. Just if I can add, Guy, thank you. I think it's very important that when you make comparison and it's true with many drugs, very often you can get a better efficacy with the drug. The problem is to get a better efficacy without impairing the safety or the side effects. And I think that's what is extraordinary is not really, I would say, that it's much more the or less active than other drug is that we get an efficacy without side effects or very, very limited side effects. Look at the terminal length rate compared to what is on the label of the drugs you have mentioned. So we could always it's always possible to get sometimes to make the patient sleep longer. The problem is that they sleep not too longer. That's the issue. So if you compare only the quantity of sleep, this is really not helpful. What is important is the quantity of sleep hand people being able to wake up in good shape. That's I would say that's the most important that people have to remember. Actually. Okay. Thank you, Al. Thank you, Al. Thank you, Al. Thank you, Al. Thank you, Greg. Operator, next question please. And the next question we received is from Nick Nieland of Citi. Your line is now open. Please go ahead. Hello. Thanks for taking the questions. The first one is about the pooled analysis. How long will that take? And will you publish the results of that? Will we see anything from that pooled analysis before you file. And then just a quick question on suicidal ideation. So although the numbers were tiny, one patient in each dose. Dave Vigo has actually got a warning on the label with a similar rate, I. E. 0.3%. So do you think that you're right to get a warning on the label or was there any comment Mike. Thank you. Thank you, Nick. Guy, I think those 2 are again for you. Some indication on the pooled analysis as to how long it's going to take us and when will we have it before the filing and then comments on the suicidal ideation. Yes. The pooled analysis is ongoing. As you can imagine, number 1, that was preplanned. So there is no big issue about that. It's ongoing. But of course, it's a bit delayed compared to the primary analysis of the study because we prioritize the 302 results before doing the pool and communicating on that. So it will take a while to have the complete data set analyzed in the full fashion. And therefore, this will come during summer. In terms of publishing it, of course, we'll publish. Now whether we publish that before filing, it's difficult to say because we are not mastering the willingness of editors to publish quickly. We will certainly make an effort to communicate in congresses as much as we can as early as we can, but I can't guarantee that it will be done before filing. We would like to prioritize the filing of everything else because we think that that's the best way to make the drug available to patients as quickly as possible. If we can have publications before, that would be great. I cannot guarantee that. On the Swiss Idol edition, I think it's very difficult to make conclusions. You see that there are a handful number of events, one hand even, not more than 4. What it means is difficult to assess. I cannot tell you what the FDA will say, But I'll be surprised if they just ignore it completely. We may be treated as every other product of that class and have the same kind of warning, that's a possibility. These effects exist. I don't think they are problematic, but the FDA rightly is often conservative in terms of what is in the labeling just to make sure that physicians and patients get the right information. But I think also, what is going to be interesting is the mood. We have a very thorough analysis on the mood effect of this drug, and I think it will be put in context. So as you said, there is always a possibility to stay safe, but what is important is will be the analysis of the effects of this drug and move. By that, Jean Paul, I think you referred to the mood domain of the ITZY questionnaire. Exactly. Right, which as I mentioned earlier, during this call, provide some very, very good data that we cannot disclose numerically, but the data were really very, very good in the first study. I don't have the results today of the second study, but the first one was very good. Great. Thank you. Excellent. Thank you, Nick. Operator, next question please. And the next question we received is from Barbara Blaha of Credit Suisse. Your line is now open. Madam, please go ahead. Thank you for taking my questions. I have two questions. One actually relates to the Type 1 error, Which you mentioned in the press release. Could you please elaborate on the Type 1 error and where it exactly occurred and whether you falsely rejected a positive or just give some details to this. And then if you pull the data together, how does How do you construct these 3 because then you don't have 16 comparisons, but only 12, you just take off Apart or yes, could you please elaborate on this? Yes. Yes. I thought I was too long on the Type I LR control in the presentation. I'll spend probably 10 minutes on that slide. I do not want to repeat everything I said. What matters is that the Type 1 error was controlled across the ANTARA study. And of course, as you can see, we didn't reject the hypothesis on LPS in the second study. We rejected the first one, which was called H2, I believe, on that slide. It limits the propagation of the alpha level downwards. It doesn't stop at all the analysis because H1 was rejected. That was a bit different from the first study where there was no rejection at all of H1 and H2 and many others as well. But I believe if you want more details rather than to spend again a few minutes, maybe we can have separate phone call. I would prefer that to you. On the pool, we don't have a typical alpha level control. And the purpose of the pool analysis is primarily to get the more precise estimate of the treatment effect on 25. But we can have a separate call because I think it can be quite complicated doing this. I will call you later. And then sorry, one more question. If the data of the pooled analysis will not reach statistical significance, Will you nevertheless file with the data that you have now or Right. Yes, this is a scenario that honestly I would reject completely. I cannot believe that at all based on the data that I've seen. I'm sorry that I cannot give you more because of the limitation due to the scientific integrity of the publication, we do not want to give P values. We do not want to give actual numbers, but if you had seen what I've seen, you'll be immediately convinced that the likelihood of the scenario you described is extremely unlikely, And I wouldn't even consider it. Okay. I hope you can believe me. Please trust me. That's all I can tell you. I will call you later. Yes. Thank you, Babura. Thank you, Guy. Operator, next question, please. Okay. Before we take the next question, just a reminder, if you would like to ask your question, please press 1 on your telephone keypad now. The next question received from Stefan Schneider of Bank Van Vogel. Your line is now open. Please go ahead. Yes. Hi, thanks. Guy, you said that in comparison to the other door as the other 2 doors on the market, you would say the night data you have seen is not impaired compared to them. Then in my view, the way I look at it that some of the label issues with the other tools is more during the daytime. So next day the next day handover effects, including driving. So my First question is, can you comment on that in comparison to the other 2? And the other one is, I think you have done the driving study. And will we see the data and if so, when? Thank you. Hi. Thank you. This is a reference question. I'm pleased that you asked it again today. Daytime, we have a very strong assessment of the daytime the next morning to use the right terminology, the morning effect. And we did that by having a special collection as part of the CDAR questionnaire. There is one question that is specifically collecting information from the patients as to whether they feel sleepy or not in the morning. And we have not again communicated visually on slides on Sonne Body, but I can comment. We don't see any sleepiness on average in this population. They tend to have less sleepiness on treatment compared to baseline that was done without treatment. And then as we increase the dose, we even see less with higher dose and lower dose and less with placebo. So overall, based on the entire data that we have and just to remind you, we have 800,000 sorry, 1800 patients in the study. The 2 studies, including 1200 on the dose on daridorexant 10, 25 and 50 milligrams. Of course, this answer database, what we see is that there is actually no impairment of the next morning effect. There is no hangover effect as we couldn't detect any hangover effect based on this specific questionnaire. And if we see a trend, it's rather the opposite that they feel better in the morning, less sleep in the morning, probably because they had actually a better night. Now the driving study is done in the same situation, but in a very, very difficult different population because as you know from the guidelines, it's done in a healthy population. We are going to report later in the year the totality of the clinical pharmacology program. We have done a very comprehensive clean pharm program looking at a number of aspects, of course, the drug drug interactions, but also the pharmacokinetic in different populations like liver impairment when impaired patients, but also the safety in specific populations like patients with obstructive sleep apnea as well as COPD patients. And of course, we have done the drug abuse study and driving studies. We would like to communicate globally on this program rather than studies 1 by 1. They are all extremely important to really define the safety profile of the product, and we do not want to just communicate on 1 and then another one and then the third one. So stay tuned. We will certainly talk about it in the near future. Thank you, Guy. Thank you, Stefan. Operator, has anybody enlisted in for further questions? So actually, we received no further questions. All right. Thank you very much. So we're coming to the end of this call. Thank you for your ongoing interest and support of Hydorsia. We are on an exciting journey, so stay tuned. Next planned communication release is for the 23rd July when we will be discussing first half financial performance. Stay safe and stay healthy. Goodbye, everyone. Operator, you can close the lines. Yes, ladies and gentlemen, thank you for your attendance. This call has been concluded. You may disconnect.