Study Update

Jun 20, 2018

Press Release

About the risks and opportunities of investing in Idorsa shares. With me today on the call are our CEO, Jean Paul Pozel our Head of Clinical Development, Guy Brownstein and afterwards during the Q and A session, we have Martine Clozell who will join us as well. They're all here to add additional color to the press release published this morning. Next slide please. So without further ado, I want to hand over to Jean Paul for his introductory comments. Thank you, Andrew. So I'd like to repeat the main strategical priorities that we have. And of course, Aprosidentan is part of this strategical vision. So what we want to do within the next 4 years sorry, next slide, is first to deliver 3 products to the market and hopefully, aprocedentan will be one of these 3. To be the commercial organization, to bring Ay Dorsia to profitability in a sustainable manner, to create a pipeline with a sales potential of over CHF5 1,000,000,000 and also to utilize state of the art technologies in all aspects of the functioning of hydroxia. But before I hand over to Guy, next slide, I'd like to describe clearly the relationship that we have with Janssen about apocitintan. So we are developing and we are collaborating with Janssen Biotech in respect to the development and the commercialization of aprocitrantan and any of its derivative compounds or products. We have received at EYDORSEA last year milestone of $230,000,000 It will be the only milestone that we are due to receive. And both Janssen and EYDORSEA have joint developing rights, but Janssen will have the sole manufacturing and commercialization rights. So this drug will be commercialized by Janssen. The development cost will be shared equally between both partners. Agroncia will oversee the Phase III development and regulatory submission for the first indication, which we are going to describe today. And afterwards, Janssen will be free to oversee and choose any additional indication. So after this description, next slide, let me hand over to Guy. Thank you very much, Jean Paul. So we are going to talk in the next few minutes about the development of apocitantin for the management of Next slide, please, Slide 7. I don't think we need to spend too much time on describing what hypertension is. I believe everyone knows what it is. Maybe just a couple of remarks. 1, that's, of course, it's cardiovascular risk factor and actually the most frequent one and one that can be normally addressable by current medicines. And these medicines have proven an effect on reducing cardiovascular morbidity and the mortality. Also, maybe important to mention that this is a very frequent condition with about 30% of the adult population presenting hypertension. However, we know that it's underdiagnosed with an estimate of 20% of hypertensive patient actually not diagnosed and not aware of their disease. The definition is changing as we speak because of new data collected from a number of clinical trials showing that the lower the blood pressure, the better in terms of the clinical outcome. And the current definition is a bit more liberal than it was before. What's probably more interesting to discuss today is the definition of resistant hypertension, which is shown on the next slide, please. So there is a definition of resistant hypertension, which means that the blood pressure remains high despite patients receiving at least 3 antihypertensive medications from 3 different classes, and this has to include a diuretic. And of course, these therapies have to be given at the maximum tolerated dose. There are a number of conditions that may look like resistant hypertension, but actually are not resistant hypertension. And I've just listed on the right hand side of the slide a number of these situations. The white coat effect, which is blood pressure taken by the physician, measured by the physician and patients being afraid, and therefore, the blood pressure will just increase because of the white coat that the physicians are wearing. So that's called the white coat effect. Medical inertia, meaning that changing therapies, increasing therapies is sometimes difficult and the adjustment of the medication to the patient needs is not always ideal. And therefore, there may be some patients that are undertreated and actually we said also underdiagnosed. As we know, adherence to treatment in chronic diseases is very frequent and this is not unseen in resistant hypertension, where there is an estimate that about 50% of the patients are actually not taking their medication properly. And also, it can happen that the blood pressure has not been measured adequately. In particular, to diagnose hypertension, we need repeated measures of that pressure being increased, and we cannot just be satisfied by one single measure. And the other possibility is that there are a number of situations, medical situation where hypertension is secondary to other conditions. And of course, then the treatment should be focused on treating the cause as opposed to just the symptoms of hypertension. And therefore, they are not included in the resistant hypertension definition. Having said that, maybe one key comment that I would add to the slide is what is the size of the population that may have resistant hypertension. And it's quite difficult to estimate it. It all depends on where the study, the epidemiological studies are performed. If you go to highly specialized centers of hypertension, you may end up with up to 30% of the patients. If you go to a more general practitioner situation, it may just be 2% or maybe 5% of the hypertensive population. So if we take 5% or 8% of the population of hypertensive patients, we still end up with millions of patients with resistant hypertension. The next slide, Slide 9, is more showing you some of the clinical characteristics of resistant hypertension as opposed to maybe extension hypertension or hypertension that is easier to treat. And now maybe a couple of points to mention here on the left hand side of the slide. This is a condition that occurs more often in elderly patients. This is very often associated with diabetes or obesity. So there are multiple risk factors that are frequently associated. We also know that we are not only called to elderly patients I mentioned, maybe a little more women than men. And also it has been suggested that the black population was more vulnerable to resistant hypertension. And maybe more important is to look on the right hand side of the slide. This graph which shows on the horizontal axis the time until major cardiovascular events are occurring and the incidence of these events on the vertical axis. And there are four lines here based on the use of the medication that the patients are treated with. And we use the number of medication as a surrogate to say the patients are more difficult to treat to control the blood pressure. You need 3 or 4, less than 3 or 4 medications or 5 medications. So what we see is that patients that are controlled on the less than 3 medications, that's a black line. There is a certain incident of these adverse events, so these major cardiovascular events. And when you need more medication to treat the patient, so 3 medications, which is a threshold for resistant hypertension or 4 or 5 or more medications, the risk of major cardiovascular events is increasing. And this shows that resistant hypertension in itself is a major contributor to the cardiovascular prognosis of the patients. So not only it's still relatively frequent, it's also a very bad prognosis element. And the question is, how can we treat these patients? And this is shown on the next slide, Slide 10, which play 2 basic approaches. The first one is very traditional pharmacological therapy. And the first thing to do, of course, is to verify that the drugs are used at the best dose, the maximum tolerated level, that, of course, the patients are compliant with the medication, they are taking it. We also need to check that the direct treatment has been optimized. And if all of that has been done, then the solution is to add additional drugs with a distinct mode of action compared to what is already given. And there are a number of proposals that have been made like antistepan receptor antagonist, beta blocker and other possibilities. So there is a possibility to control patients with more than 3 medications, 4, 5 or more. But of course, this can become quite complicated. More recently, there is this practice of renal denervation that has been suggested. I would just like to point out that this new potential therapy has so far not be fully validated in randomized clinical trials. And therefore, some of the experts, as quoted on the bottom of the slide, is that there is an urgent need to find additional therapies, especially if they act on a different pathway and therefore can bring complementarity to the drug that are already being used for this condition. Now I would like to tell you why we think afrostatantan has a place in the treatment of resistant hypertension. And I will start with Slide 11, next slide please, which shows the role of angiotelin in the pathophysiology of resistant hypertension. And we know that the insulin system is activated, especially in salt and volume different hypertension on one side. And on the other side what we know is that resistant hypertension is often a salt and volume dependent hypertension. So there is therefore a pathophysiological logic to block that system to control the different hypertension. We also know that there is a broad role of underprelin. We have many physiological processes in the body. And there is an expectation that by working that system, we may have an impact on that we are remodeling kind of hypertrophy and therefore to address some of the complication of the distant hypertension. We don't go into details. But there is a very clear rationale in terms of comfortable pressure and also presenting the delayed complications of treatment hypertension. Of course, the question then is what is occlusiveentan in respect to on the tailing, and that's showed on Slide 12, next slide, which shows some of the characteristics of cotociphentam. 1st, it's a dual AT ATB receptor antagonist and at the dorsal, we believe that it's important to block the 2 receptors. We have shown in animal models that it has a synergistic effect with both guarantee hypertensive drug using resistant hypertension. And there is, of course, the demonstration manual model of the effect of a positive time under pressure. Maybe also interesting to look on the right side of the slide. It's an already active product, which of course makes the life of patients easier than it was. There is a low potential for drug drug interaction coming from in vitro and some of the individual studies we have completed so far. We have human evidence that it's blocking BOS receptors, which we knew from test tube experiments concerning human. And final point is that we have a direct demonstration that apocitamantana is actually decreasing blood pressure of essential hypertension, and that's a Phase II study that I will describe to you in a few moments. So in the next slide now is showing you what we have done so far and where we want to go in terms of the clinical development. The clinical pharmacology package is, I can say, complete. As I said before, we have this confirmation of dual blockage of ETATV. We know that we have not need a degree of renal impairment, which is important because retinal function is frequently associated with hypertension, especially So this we can see, clean farm done. We also did the Phase II study, and we have demonstrated a clinically relevant dose dependent lowering blood pressure in the central hypertension patients. And we have been able to select the dose of further development based on the Phase 2 study. In parallel to the Phase 2, we did a survey, a very large survey worldwide called SPIRIT. And the purpose of the survey was to characterize the resistance hypertension patient population in respect to a number of clinical characteristics as well as the therapies the patients are taking. And it was also used to identify the sites, investigator sites where these patients could be found as a support to accelerate the recruitment of the patient later on in the Phase III functional study. So before moving on to the Phase III study description, I would like to come back to the results of the Phase II. Next slide is Slide 14, showing the design of the trial, the classical 8 week treatment with placebo 5, 10, 25 or 15 milligrams with a positive control within the 3 20 milligram. So this is a very classical design. There was a period of screening and rolling at the beginning, but we found period and then a withdrawal period and the safety follow-up. This was prospective in standard, double blind, randomized. The drug was tested as monotherapy. And the patient population were mild to moderate potential hypertension with the definition that is shown here with a need to confirm at randomization that the blood pressure will still increase. What the next slide is showing, Slide 15, actually the results of the primary endpoints of the diastolic blood pressure on the left, on the systolic blood pressure, which shows the main secondary endpoint on the right. We see on the horizontal axis of this graph the different doses, placebo on the left and 5, 10, 25 and 50 milligrams of apocitam tag and then as a separate column, the lesion occluder. And what we see on the vertical axis is a mean change from baseline in the blood pressure, diastolic on the left and systolic on the right graph. What we see is that there is a very nice dose response with increase in the decrease of blood pressure on 5,1010,025 milligrams, which is a plateau with no further benefit of increasing when we increase the dose from 25 to 15 milligrams neither on the blood the diastolic blood pressure nor on the systolic blood pressure. What we see as well is the effect of lisinopril at the dose of 20 milligram, which is an efficacy roughly at the level of 10, maybe between 5 10 milligram of per second. So that's on the efficacy side. We are very happy to see this very nice dose response. And of course, it's important to cross this data with the safety profile of the product, which is displayed on the next slide, Slide 16, where we see again placebo in the first column and 5, 10, 25 and 50 milligrams in the 6 different columns and the last one being lisinopril. And we see the different side effects, starting with headache and mesopharyngitis, etcetera. What we see really is that the number of patients with adverse events is pretty small. There is no dose response for any of these adverse events and the tolerability of the system tolerability at first time seems to be very good across the dose range that was studied in the trial. So therefore, at this stage, we have some conclusions. Next slide, Slide 17. On the efficacy side, the dose response was consistent across all parameters measured. I showed you the systemic and diastolic blood pressure, There are a number of ways to measure it. There is ambulatory blood pressure. There is the office based blood pressure. All the parameters show the same efficacy curve. The efficacy was observed at 10 milligrams and no additional effect was observed at a higher dose 15 milligram, Something that I didn't mention that we got from the ambulatory blood pressure covering 24 hours, the effect of aprocedentan was observed during the entire 24 hour period. And from a safety perspective, of course, the limitation of the study design and the sample size, we can conclude that all doses were well tolerated and the probable treatment of that event was similar to what was observed in placebo. So at the end of this Phase II, we could quite securely conclude that 12.5 milligrams and 25 milligrams is there some more exploration, And these are the bodies that we have selected for the Phase III program. So these are the data that we have so far. Now let's look at the Phase III, and that's starting the next slide, Slide 18. The precision study with, I said, the short term efficacy of apositam time as well as the durability of the effect. And in doing so, we will provide replication of clinical evidence in a single study. And this is the level of evidence that we need to provide for regulatory approval. The next slide, Slide 19, is showing the design. It may appear a little complicated, but we can go step by step from the left to the right. So we will start with a screening period in purple here, where patients with resistant hypertension, based on the initial claim, patients that have hypertension on background medications are entering this period. And at some point during that period, the patients are going to be switched to standardized therapy. I will come back to that in a moment. And then under the screening period in blue here, And then there is a running phase where we want the patients not only to be on standardized medication, but we also want them to have confirmed hypertension, the blood pressure is not sufficiently controlled and there has to be the blood pressure has to be stable. So during the run-in, we verify that the patients are on this standardized medication, they are stable from a blood pressure perspective and the blood pressure is still increased compared to the normal. And then the patients will enter into a 3 part treatment phase, Part 1 followed by Part 2 and then Part 3. The Part 1 is lasting for 4 weeks, and the patients will get 25 milligram or 12.5 milligram of placebo in a randomized manner. After 4 weeks, everybody will be placed on a dose of 25 milligram. And then after 32 weeks of the treatment, the patient will be re randomized to either approximately 25 milligrams of placebo in what we call the withdrawal period, Part 3, and this will be followed by a very traditional safety follow-up of the matter. During the entire study, starting from the time patients are switched to the standardized background therapy, as indicated by the blue line on the bottom of the slide, the patients will continue their background therapy, which will be described in the moment. The next slide is maybe giving you a little bit of a precision of what the objectives of the different parts are. So Slide 19, we see that the Part 1 is a double blind treatment, comparing a 12.5, 25 and placebo for a total of 4 weeks. And the purpose of that is to demonstrate the blood pressure lowering effect of a first time when added to the standard of care, which is the standardized medication, in true resistant hypertension. So by having selected during the screening the running period of the true resistant hypertension, we place them on some of that medication. We can now securely show that 12.5 and or 25 milligram of our prostaglandin are superior for placebo in controlling the blood pressure. This will provide the first evidence of an efficacy of the product. Then the part 2, all the patients in a single line manner will be treated by 25 milligram of apacitam10 for 32 weeks. The purpose being really to evaluate the long term safety and tolerability of apacitam10, of course, to confirm the Phase 2. And then the 3rd part of the study, patients that have reached that point will be re randomized to receive either 20 milligram as possible and placebo for a better 12 weeks. And this will be a show of the opportunity to demonstrate the effect of blood pressure is durable. In other words, when the patients have randomized to placebo, the control of blood pressure will disappear. And when the patients are continuing on 25 milligrams, then the blood pressure will still be under control. And by doing that, we will have repetition of efficacy assessment, which in complement to the observation in Part 1, we provide royalties from a regulatory perspective. So that's the design, the objectives. Now let's look quickly at the population. So at entry next slide 21. At entry, the patient has to have blood pressure increased and we put a threshold of 140 millimeters of mercury measured by automated pressure measurements. This automated the pressure measurement is designed to avoid the white coat effect to the patients are put in a room with the device that is measuring blood pressure and the physician is not standing next to them. And therefore, we think that it's a better way of measuring the weight of the pressure. And of course, this occurs when the patients are on 3 different pharmacologic classes, including direct as they have a definition of the different hypertension. And then, as I said earlier, into the screening period, at some point, we switch to standardized therapy, which is made of 3 drugs, calcium channel blocker, which is amodipine, and mongipatin receptor blocker, which is Vazartan, and then a directive, which is a local hospital. The patients coming to the run-in, they have been switched adequately to the standardized limitation and the blood pressure, again, by AODPM is still above the threshold. And then during the run-in period, we will again verify the stability at a high level above 140 millimeter of mercury of patients. And therefore, at the end of the run-in, if they still meet this criteria, they are on some of that therapy and they still meet the blood pressure criteria, they can be randomized. The next slide is Slide 22, showing the endpoints of the study. So very traditional, the primary endpoint, the change from baseline to week 4 during the first initial part, the Part 1, after 4 weeks of double blind treatment in the systolic blood pressure measured by AVPN. And a number of other endpoints, a key secondary endpoint will be the same kind of measure for weeks after the start of the withdrawal period, the Phase 3, and that will be the provide the confirmation of the efficacy and the durability of the effect. And then there will be some further measures of blood pressure at different time points between week 4 week 40 of diastolic blood pressure by LVPM as well as systolic and diastolic blood pressure by 24 hour ambulatory blood pressure monitoring. And of course, as normal, the safety assessment will be done along the entire study as well as pharmacokinetic assessment at some decided time points. So that's what we are now doing. And the first patient have been screened. We announced that this morning. So now you know what we have done. You know what we are doing. And we can just summarize on the next slide what we where we are. So maybe the first point, the second bullet point, that we did collaboration with Jenssen Biotech, which Jean Paul has detailed earlier. But maybe a conversant perspective, maybe important to tell you why we are so confident in this program in resistant hypertension and the ability to have positive time to provide the benefits of a normal once daily new treatment based on the pathophysiology of atoracitin hypertension, a lot of action of atoracitin time, the efficacy we have observed in Phase 2. And the comprehensive Phase 3 study, which is going to look at efficacies from the short term as well as long term perspective and also looking at the safety during long term initiation. And finally, just to mention that this registration program has benefited from inputs from the The first question is from Richard Parks of Deutsche Bank. Your line is now open. Please go ahead. Hi. Thank you very much for taking my questions. Hopefully, you can hear me okay. I've just got 3 questions. Firstly, obviously, other endothelin antagonists have been impacted by incidence of edema in resistant hypertension studies. And we know that procyutantin's pair of molecules obviously got a low edema risk. But I wondered if you could talk about the similarities and differences from a pharmacological basis between a Procytentan and MACI-ten ten, maybe how its limited renal excretion in long half life might further improve that edema profile relative to its parent molecule. So that's the first question. Maybe I'll take them sequentially. Okay. So I think Guy, you open up and then we'll hand it over to Martin. Right. I can tell you about the clinical observation, which is honestly very little in terms of edema. We have quite a lot of knowledge about the edema manifestations with the receptor antagonist based on the many years of work that the other people have done in their previous company, Helion. And with apocitantan in the resistant hypertension as it's we have a case as well But I think the explanation is actually coming from the mechanism of action, and Marcin is going to tell you why we have that very interesting observation. Yes, thank you, Guy. It's about 30 years of work of research where we have really tried to elucidate the whole of the Bose receptors in pathological situations. And we have really understood that for chronic indications, it's important to block both receptors, but it's also it's giving a big difference. And we have published preclinical data, which are explaining that when there is no blockade of both receptor, but only 1, you have potential relative activation and imbalance, which activates receptor, antibody receptors in different parts of the body and the kidney in particular. And you have the risk of stimulating and increasing vascular permeability and that can cause edema. And therefore, we have put forward many years ago the hypothesis was that with dual antagonist, we might have a low risk of edema. And I think that over time so far, that has been confirmed in clinical situation. Right. So we see on the safety slide that I showed, there are a couple of cases at the top doses, but we didn't observe any weight increase in the trial content of placebo. So it's not that we have 0, 0, but in general, I think we have seen very modest in number and Richard, do you have other questions? Yes. I just wondered if there are any measures being taken to exclude patients from the Phase III trial that might be at increased risk of edema, such as patients with renal impairment or incipient heart failure? I wonder if there's any measures there. And then I mean, if we can take the third was, can you talk about what's included in the trial design over how edema events will be managed in terms of diuretic dose adjustments? Thank you. I hear you're asking quite a lot of details on the protocol, which I may not have all in mind right now. But yes, of course, we exclude some of the patients. We're going to be as broad as we can. The renal function, we have to, of course, exclude maybe the most severe one. And there are some stability criteria in terms of the heart function at the beginning. In terms of how we monitor them, of course, the weight is going to be monitored as well as the adverse events. And ideally, we would like to limit the flexibility in terms of the direct EQs because otherwise, it's affecting in itself the blood pressure, and this will confirm the effect. Perfect. Thank you. Thank you, Richard. Operator, next question please. The next question is from Vincent Meunier of Morgan Stanley. Your line is now open. Please go ahead. Thank you for taking my question. I mean the first one is on the trial design. Would it be possible to submit at the end of the Part 2 of the study? And the second question on the trial is, do you plan to launch a long term study looking at CB outcomes and maybe end organ protection? And the third question is more related to the costs. Can you give an estimate of the total cost of the Phase III? I know it's fifty-fifty shared with G and J. And maybe also if you can make a breakdown of that cost. And as well, should we link this to the recent comments to seek new funding in 2019 to support late stage trials? Okay, Guy. I think I'll start with the last one. I think Okay. I'll take the last one very quickly. So on the cost description, you remember when we announced the in licensing by J and J where of the $230,000,000 $160,000,000 were immediately revenue generating, whilst the remainder were deferred. That deferred part represents in rough what our cost could be if modeled. And I think those assumptions are still valid. With regards to recent comments in the press, I don't think at this point in time we are in a position that we want to comment on that. Over and above that we have said in the past that we are not financed to breakeven and those comments remain. Otherwise, Guy? Right. So on the second question, the long term, of course, it's interesting scientifically and medically, but it's not needed from a regulatory perspective. So at the moment, what we do is to focus on developing a package that will be satisfactory to the regulators. And for that, what we need is to demonstrate an effect on the blood pressure and this effect is durable, which the study is addressing. At a later time point, it may become necessary or useful to embark into a long term event driven study. But of course, as you can imagine, this has to be large, long and placebo controlled to be interpretable. And therefore, there has been no decision made so far to do that. The first one was about the Part 2, and I can't remember what it was Can the trial be stopped at the end of the Part II? Patients? Yes, the trial. Can the trial be stopped at the end of Part II? No, no. The Part 3 is an integrated part of the protocol. It's only one study. That's why we have shown the design on the Slide 19, if you want to go back to your slide. And of course, what will happen is that we start with many patients at the beginning and some will not continue probably we have the dropout as always in clinical trials. So there will be less patients entering into Part 3 than Part 2 unless Part 2 than Part 1. But the study is fully powered, and we calculated backward the sample size to be sure we have enough patients in Part 3. Now the study is not going to start after Part 2. And actually, there is no reason to do so because the results of Part 1 will not be known before the end of the trial. So there would be no basis for potentially stopping early. Okay. Thank you very much. Thank you, Vasyl. Operator, next question please. The next question is from Peter Welford of Jefferies. Your line is now open. Please go ahead. Firstly, just on the safety profile in the Phase 2, I wonder if you could detail what the 2 serious adverse events were on the 25 milligrams and whether either of those were cases of edema. Secondly then, just on the screening phase, what sort of assumptions have you made with regards to what number of patients would be required to enter screening in all likelihood to get to the circa 600 you're aiming for at the actual start of the randomized phase? Thirdly then, is there any possibility in the trial sorry, is there any possibility in the trial protocol for patients who can't tolerate 25 milligrams in Part 2, who obviously been titrated from placebo or the lower dose, to use the lower dose at all of afrostatantan? Or if patients can't tolerate the 25 higher dose, are they forced then to withdraw from the study at that point? And so just finally, is ischemic heart disease excluded from the study given that the fixed dose that needs standard protocol has been used during the screening? Thank you. Okay. So I'm not sure I remember all the questions, but taking the third one, I think that you raised, which is the patient that do not study during the Part 2. No, there will be no titration down. And the reason being that it's complicated to operationalize and as well as we wanted to have 25 milligram as the key dose to ensure that the safety will be properly collected at the top dose that we are considering for registration. And there will be no possibility for patients to go back to either 12 point 5 or placebo. So long term, 20 25. The first one, I must say that I don't have on the top of my head the detail of the sales adverse event. I should have put that as a footnote on the slide. That's clear. Thanks for asking. And I think it will be communicated in terms of communications at some point. I'm sure there was nothing of concern, but I can't remember what they were. I'm sorry for that. And the second question, Andrew, if you can How many patients do we need to screen to get to the 2 100 patients roughly? Yes. I will know that at some point in the trial when we see the screen failure rate. We have some estimates that probably we have to screen 2 to 3 times more, if not more, maybe up to 10 times, who knows. It's very, very difficult to know at this stage. We are ready to screen many. And the exact number, we'll find out when we see the dropout during the screening period. We have done enough work in the SPIRIT survey to sort of identify sites. When we did the survey, we identified sites and we and patients in these sites up to more than 1500 patients. These are not the patients that are going to enter the trial, but it means that we have identified sites that can provide this kind of number. So in my view, counting on 2 to 3 times would be a reasonable assumption at this stage. It all depends on how the patients have been characterized before screening by the sites. If we work with highly specialized centers, probably we can't screen less because they're already very well characterized. And that's why we one of the reasons why we did the SPIRIT survey to try to really identify the sites that can provide this population. And then we can minimize maybe the number of patients screened. But we'll be a lot more comfortable to see that when we have a better view on the screen for you, right? And the last one, question 4, Andrew? Ischemic heart disease, is that excluded? Not completely, I believe. And actually, patients can, for example, receive in addition to the 3 medications, beta blockers, which is often used in ischemic heart disease. Of course, recent acute ischemic events are excluded with a period of 6 months, But chronic, stable or ischemic disease or ischemic events occurring much earlier than that would not be extremely clearly in the trial. That's great. Thank you. Thank you, Peter. Operator, next question please. The next question is from Ram Selvaraju of H. C. Wainwright. Your line is now open. Please go ahead. Hi, thank you for taking my questions. This is Julian on for Ram. First, is there any guidance at this time regarding how long enrollment is expected to take for Precision? No. And as I say very often, if I give you some time lines and we're actually much faster than that, I would be in trouble that we don't want to take that risk. And it's linked to the previous question, I think, in respect to the dropout during screening. It really depends on how well characterized the patients are at the beginning. And that's why we did the SPIRIT survey to identify sites that are dealing with this population. Now we know them, and we initiate the study in deciding priority with the aim of recruiting as fast as possible. Whether it will take 6 months, 12 months, 18 months, I just cannot tell you. And it's only when we see the recruitment curve that we'll be able to define that more carefully. It also depends on the possibility to initiate how much familiar you are with the complexity of initiating clinical trials these days. But there are a number of hurdles in respect to site initiation due to regulatory approvals, it should come with approvals and contracts we have to establish with the site and the institution. This can take sometimes quite a bit of time. And therefore, the secret for faster treatment is, number 1, to pre identify sites through activities like the survey we have done and number 2, to try to initiate the site as fast as possible. And this is what the team is very busy with at the moment. Got it. Understood. And for my second question, I was just curious if there are any notable differences in enrollment criteria or run-in protocols between precision and the completed Phase 2 program? Yes. The Phase 2 was done in hypertension, not in resistant hypertension. And this one is done in a very well characterized resistant hypertension. So that's a major difference in terms of the population. The rest is actually very similar because the endpoint and the treatment and the rest is very much the same. But of course, the population is different. Great. Thank you for taking my questions. Thank you, Julien. Operator, next question please. The next question is a follow-up from Richard Park, Deutsche Bank. Your line is now open. Hi, thanks for taking my follow ups. I've just got 2 or 3. The first one is just on the clinical trial design. I think if I understand the trial design correctly, you're only going to have placebo controlled safety data on for Part A and Part C or Part 1 and Part 3, which would limit that to relatively short duration of placebo controlled safety data. I just wondered if you've got agreement with the regulators that, that would be sufficient given that it's going to make delineation of any kind of signals of edema risk, etcetera, more difficult to necessarily attribute to the drug versus the background patient population? And then secondly, I just wondered if you could talk about the choice of automated in office blood pressure measurement assessment versus use of ambulatory blood pressure measurement in order to reduce risk of confounding from placebo effects? I'm just interested around that the choice between those two options and why you went for the automated in office? Yes. So on the first question, yes, you are correct that there will be a time limitation in terms of the safety assessment in comparison to placebo, the 1st 4 weeks and then the last 12 weeks. This design has been discussed at length with the regulators. And there was never a concern of interpretation during that discussion. You mentioned specifically in the evolution of edema, which may, of course, become more complicated because some of the background medication are actually associated with edema like Remodipine. Having said that, there was a comment made earlier by Martin and me about how we see edema, the risk of edema in this study. But what we know as well from work that has been done here, reason for the second one is that if they might occur, they normally occur relatively quickly after treatment. And therefore, we would see that in the double blind part 1. Then the choice of the instrument or the methodology for blood pressure, yes, we could do ambulatory blood pressure or we could do a OVPM. Our perception was regulatory wise, maybe OVPM was the best. This, I think, is debatable. But at the end in the end, both of them are being done. And from the experience we have from the Phase II, the data are extremely similar. It would be extraordinary to see a wonderful effect on one and no effect on the other one or the opposite. So we really don't expect that to occur. Both of them are going to be done. And we just prioritize automated office question measurement as a very reliable method and a standard, very easy to conduct standardized methodology across all centers. No need to have complicated equipment on the patient body. So there are a number of reasons why we think it's a very reliable, easy to implement measure. Okay. Perfect. And then just one final follow-up, just about further development of the compound. Obviously, there's multiple other possible indications, including diabetic nephropathy. Is that should we think about decisions on future development maybe be dependent on the results of this clinical trial program? Or could additional clinical studies and other indications start before then? Thanks. Yes, Richard. I mean further indications are options that Johnson and Johnson has. So I think it is best if you go and ask them what they will envisage and decide going forward. Okay, perfect. Thank you. Thank you, Richard. Operator, next question please. The next question is from Maria Maldonado from Deutsche Bank. Your line is now open. Please go ahead. Hi, thanks for taking my question. Just one. I was wondering if you could make some comments about how you envision the positioning of aprositantan and in particular potential competition from spironolactone. I'm wondering do you see these drugs competing against each other as being the sort of the first drug of choice for the 4th drug? Or do you see a proscitentan being relegated more to the spironolactone patients or to the contraindicated patients that you mentioned? Thanks. Thank you, Maria. Jean Paul, I think you want to take this one. I think just spironolactone has not been indicated in this type of patients. So it's really with this drug will be the 1st drug really studied and approved for this indication. And I think that we are testing this drug in a lot of patients with diabetes, with renal dysfunction and with very high risk of hyperkalemia that you can see with this peonolactone, especially that you see that today a lot of diabetic patients are treated with SGLT SGLT2 type of compounds, which are direct also. So since all patients will be already under one direct, I think that the patients we are testing are not really the best candidate with spironolactone. So I think that we really don't think that this compound or apresidantan will compete with spironolactone. Great. Thank you very much. Thank you, Marianne. Operator, next question please. There are currently no further questions. Haven't received any further questions. I'll hand back to you, Andrew. Thank you. So if there are no more questions, I think we therefore come to the end of this update on APOCITON-ten. This also marks the last presentation in this series of updates that we've scheduled and announced that will be coming during the course of the first half of the year. So next scheduled event will be the first half results expected on the 24th July. Thank you for your continued interest and your support in Vydorsia. Operators, please close down the lines.