informed about the risks and opportunities of investing in Idorsia shares. With me today on the call are our CEO, Jean-Paul Clozel, our Head of Clinical Development, Guy Braunstein, and afterwards, during the Q&A session, we have Martine Clozel will join us as well. They're all here to add additional color to the press release published this morning. Next slide, please. Without further ado, I want to hand over to Jean-Paul for his introductory comments.
Thank you, Andrew. I'd like to repeat the main strategical priorities that we have, and of course, aprocitentan is part of this strategical vision. What we want to do within the next four years, sorry, next slide, is first to deliver three products to the market, and hopefully aprocitentan will be one of the three. To build a commercial organization. To bring Idorsia to profitability in a sustainable manner. To create a pipeline with a sales potential of over CHF 5 billion, and also to utilize state-of-the-art technologies in all aspects of the functioning of Idorsia. Before I hand over to Guy, next slide, I'd like to describe clearly the relationship that we have with Janssen about aprocitentan.
We are developing and we are collaborating with Janssen Biotech in respect to the development and the commercialization of aprocitentan and any of its derivative compounds or products. We have received at Idorsia last year a milestone of $230 million. It will be the only milestone that we are due to receive. Both Janssen and Idorsia have joint developing rights, but Janssen will have the sole manufacturing and commercialization rights. This drug will be commercialized by Janssen. The development cost will be shared equally between both partners. Idorsia will oversee the phase III development and regulatory submission for the first indication, which we are going to describe today. Afterwards, Janssen will be free to oversee and choose any additional indication. After this description, next slide, let me hand over to Guy.
Thank you very much, Jean-Paul. We are going to talk in the next few minutes about the development of aprocitentan for the management of resistant hypertension. Next slide, please. Slide seven. 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. One, that, of course, it's a cardiovascular risk factor and actually the most frequent one, and one that can be normally addressable by current medicines. These medicines have proven an effect on reducing cardiovascular morbidity and 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 patients 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. There is a definition of resistant hypertension, which means that the blood pressure remains high despite patients receiving at least three antihypertensive medications from three different classes, and this has to include a diuretic. 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. 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. 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 need is not always ideal. 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. Also it can happen that the blood pressure has not been measured adequately.
In particular, to diagnose hypertension, we need repeated measures of blood pressure with increase. We cannot just be satisfied by one single measure. The other possibility is that there are a number of medical situations where hypertension is secondary to other conditions. 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? It's quite difficult to estimate it. It all depends on where 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 room situation, it may just be 2% or maybe 5% of the hypertensive population. 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 nine, is now showing you some of the clinical characteristics of resistant hypertension as opposed to maybe essential hypertension or hypertension that is easier to treat. 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 all equal.
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. 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. 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 less than three or four medications or five medications.
What we see is that patients that are controlled on less than three medications, that's a black line, there is a certain incidence of these adverse events or these major cardiovascular events. When you need more medications to treat the patient, three medications, which is a threshold for resistant hypertension, or four or five or more medications, the risk of major cardiovascular events is increasing. This shows that resistant hypertension in itself is a major contributor to the cardiovascular prognosis of the patients. 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? This is shown on the next slide 10, which display two basic approaches.
The first one is very traditional pharmacological therapy, 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 and are taking it. We also need to check that the duration treatment has been optimized and if all of that has been done, the solution is to add additional drugs with a distinct mode of action compared to what is already given. There are a number of proposals that have been made, like angiotensin receptor antagonist, beta blocker, and other possibilities. There is a possibility to control patients with more than three medications or five or more. 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 these newer potential therapies have so far not been fully validated in randomized control trials. 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 drugs that are already being used for this condition. Now I would like to tell you why we think aprocitentan has a place in the treatment of resistant hypertension and I will start with slide 11, which shows the role of endothelin in the pathophysiology of resistant hypertension. Next slide, please.
We know that the endothelin system is activated especially in salt and volume-dependent hypertension on one side and on the other side, what we know is that resistant hypertension is often a salt and volume-dependent hypertension. There is therefore a pathophysiological logic to block that system to control resistant hypertension. We also know that there is a broad role of endothelin, involved in many physiological processes in the body, and there is an expectation that by blocking that system, we may have an impact on vascular remodeling, cardiac hypertrophy. Therefore, to address some of the complications of resistant hypertension without going through details. There is a very clear rationale in terms of controlling blood pressure and also preventing the delayed complications of resistant hypertension. The question is, what is aprocitentan in respect to amlodipine? That's shown on slide 12. Next slide.
Which shows some of the characteristics of aprocitentan. First, it's a dual ETA/ETB receptor antagonist. At Idorsia, we believe that it's important to block the two receptors. We have shown in animal models that it has a synergistic effect with other anti-hypertensive drugs used in resistant hypertension. There is, of course, the demonstration in animal models of the effect of aprocitentan on blood pressure. Maybe also interesting to look on the right side of the slide. It's an orally active product, which of course makes the life of patients easier than, of course, if they are administered by other routes of administration. There is a low potential for drug interaction coming from in vitro and some of the in vivo studies we have completed so far. We have human evidence that it's blocking both receptors, which we knew from test tube experiments concerning human.
Final point is that we have a direct demonstration that aprocitentan is actually decreasing blood pressure in essential hypertension. That's a phase II study that I will describe to you in a few moments. 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 preclinical pharmacology package is, I can say, complete. As I said before, we have this confirmation of dual blockage of ETA/ETB. We know that we have a degree of renal impairment, which is important because decrease in renal function is frequently associated with hypertension, especially resistant hypertension. There is, as I said, as well, low potential for drug interaction coming from preclinical and clinical pharmacology studies. This we can tick, clinical pharmacology done.
We also did a phase II study, and we have demonstrated a clinically relevant dose-dependent lowering of blood pressure in essential hypertension patients. We have been able to select the dose for further development based on the phase II study. In parallel to the phase II, we did a survey, a very large survey worldwide, called SPIRIT. The purpose of the survey was to characterize the resistant hypertension patient population in respect to a number of clinical characteristics, as well as the therapies the patients are taking. It was also used to identify the investigator sites where these patients could be found as a support to accelerate the recruitment of the patients later on in the phase III clinical study. 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, very classical, 8-week treatment with placebo, 5, 10, 25 or 50 milligrams with the positive control lisinopril 20 milligrams. This is a very classical design. There was a period of screening and learning at the beginning, the treatment 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. The patient population were mild to moderate essential hypertension with the definition that is shown here, with a need to confirm at randomization that the blood pressure was still increased. What the next slide is showing, slide 15, actually the results of the primary endpoint, the diastolic blood pressure on the left, and the systolic blood pressure, which was the main secondary endpoint on the right.
We see on the horizontal axis of this graph the different doses, placebo on the left, 5, 10, 25, and 50 milligrams of aprocitentan, and then as a separate column, the lisinopril. What we see on the vertical axis is the 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 a decrease in blood pressure on 5 and then 10 and 25 milligrams, reaching a plateau with no further benefit of increasing when we increase the dose from 25 to 50 milligrams, neither on 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 milligrams, which is the efficacy, roughly the level of 10, maybe between 5 and 10 milligrams of aprocitentan. That's on the efficacy side. We are very happy to see this very nice dose response. Of course, it's important to cross this data with the safety profile of the product, which is displayed on the next slide 16, where we see again, placebo in the first column, then 5, 10, 25, and 50 milligrams on the subsequent columns, and the last one being lisinopril. We see the different side effects, starting with headache and nasopharyngitis, et cetera. 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 for aprocitentan seems to be very good across the dose range that was studied in the trial. Therefore, at this stage, we have some conclusions. Next slide 17. On the efficacy side, the dose response was consistent across all parameters measured. I show you the systolic and diastolic blood pressure, but there are a number of ways to measure it. There is the ambulatory blood pressure, there is the office-based blood pressure. All the parameters show the same efficacy curve. The efficacy was observed at 10 and 25 milligrams, and no additional effect was observed at a higher dose, 50 milligrams. Something that I didn't mention that we got from the ambulatory blood pressure covering 24 hours, the effect of aprocitentan was observed during the entire 24-hour period.
From a safety perspective, of course, with the limitation of the study design and the sample size, we can conclude that all doses were well-tolerated, and the overall frequency of adverse events was very similar to what was observed in placebo. At the end of this phase II, we could quite securely conclude that, 12.5 and 25 milligrams deserves some more exploration. These are the doses that we have selected for the phase III program. These are the data that we have so far. Let's look at the phase III, and that's starting the next slide 18. The PRECISION study will assess the short-term efficacy of aprocitentan, as well as the durability of the effect. In doing so, we'll 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 19, is showing the design. It may appear a little complicated, but we can go step by step, from the left to the right. It 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 to this period. 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. Under the screening period in blue here, 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 the blood pressure has to be stable.
During the running, we verify that the patients are on the standardized medication, they are stable from a blood pressure perspective, and the blood pressure is still increased compared to the norm. The patients will enter into a three-part, treatment phase, part 1, followed by part 2, and then part 3. Part 1 is lasting for 4 weeks, and the patients will get 25 milligrams or 12.5 milligrams of placebo, in a randomized manner. After 4 weeks, everybody will be placed on a dose of 25 milligrams. After 32 weeks of that treatment, the patient will be re-randomized, to either aprocitentan 25 milligrams or placebo, in what we call the withdrawal period, part 3. This will be followed by the traditional safety follow-up of the month.
During the entire study, starting from the time patients are switched to the standardized background therapy, as indicated by the blue line at the bottom of the slide, the patients will continue their background therapy, which will be described in a moment. The next slide is maybe giving a little bit of a precision of what the objectives of the different parts are. Slide 19, we see that part 1 is a double blind treatment, comparing 12.5, 25, and placebo for a period of 4 weeks. The purpose of that is to demonstrate the blood pressure lowering effect of aprocitentan when added to the standard of care, which is the standardized medication, in true resistant hypertension. By having selected during the screening and the running period, the true resistant hypertension, we place them on standardized medication.
We can now securely show that 12.5 and/or 25 mg of aprocitentan are superior to placebo in controlling blood pressure. This will provide the first evidence of an efficacy of the product. The part two, all the patients in a single blind manner will be treated by 25 mg of aprocitentan for 32 weeks. The purpose being really to evaluate the long-term safety and tolerability of aprocitentan, and probably to confirm the safety profile we observed from phase II. The third part of the study, patients that have reached that point will be re-randomized to receive either 25 mg aprocitentan or placebo for a period of 12 weeks. This will give us the opportunity to demonstrate that the effect on blood pressure is durable.
In other words, when the patients are randomized to placebo, the control of blood pressure will disappear, when the patients are continuing on 25 mg, the blood pressure will still be under control. By doing that, we will have repetition of efficacy assessment, which in complement to the observation in part one, will provide the activity from a regulatory perspective. That's the design, the objectives. Let's look quickly at the population. At entry, next slide, 21. At entry, the patient has to have blood pressure increased, and we put a threshold of 140 millimeter of mercury, measured by automated office blood pressure measurement. This automated office blood pressure measurement is designed to avoid the white coat effect. The patients are put in a room, with a device that is measuring blood pressure, and the physician is not standing next to them.
Therefore, we think that it's a better way of measuring the real blood pressure. Of course, this occurs when the patients are on three different pharmacologic classes, including diuretic, as the definition of resistant hypertension. Then, as I said earlier, into the screening period, at some point, they will be switched to a standardized therapy, which is made of three drugs, a calcium channel blocker, which is amlodipine, angiotensin receptor blocker, which is olmesartan, a diuretic, which is hydrochlorothiazide. The patients can enter the run-in if they have been switched adequately to the standardized medication and their blood pressure, again by ABPM, is still above the threshold. During the run-in period, we will again verify the stability at a high level, above 140 millimeters of mercury of patients.
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 endpoint of the study. Very traditional. The primary endpoint, the change from baseline to week four during the first initial part, the part one, after four weeks of double-blind treatment in the systolic blood pressure measured by ABPM. There are a number of other endpoints. A key secondary endpoint will be the same kind of measure four weeks after the start of the withdrawal period, the period three, that will provide the confirmation of efficacy and durability of the effect.
Then there will be some further measures of the blood pressure at different time points between week four and week 40 of diastolic blood pressure by ABPM, as well as systolic and diastolic blood pressure by 24-hour ambulatory blood pressure monitoring. Of course, as normal, the safety assessments will be done along the entire study, as well as pharmacokinetics assessment at some decided time points. That's what we are now doing, and the first patients have been screened. We announced that this morning. Now you know what we have done, you know what we are doing, and we can just summarize on the next slide where we are. Maybe the first point is the second bullet point. There will be collaboration with Janssen and Idorsia, which Jean-Paul has detailed earlier.
Maybe from a scientific perspective, maybe important to tell you why we are so confident in this program in resistant hypertension and the ability of aprocitentan to provide the benefit of an oral once-daily new treatment based on the pathophysiology of resistant hypertension, the mode of action of aprocitentan, the efficacy we have observed in phase II. The comprehensive phase III study, which is going to look at the efficacy from a short-term as well as long-term perspective, and also looking at the safety during long-term administration. Finally, just to mention that this whole hypertension program has benefited from inputs from the
Gentlemen, we will now begin our question and answer session. If you have a question for our speakers, please dial zero one on your telephone keypad now to enter the queue. Once your name has been announced, you can ask a question. If you find your question is answered before it is your turn to speak, you can dial zero two to cancel your question. If you are using speaker equipment today, please lift the handset before making your selection. One moment please for the first question. The first question is from Richard Parkes 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.
Very good.
I've just got three questions. Firstly, obviously, other endothelin antagonists have been impacted by incidents of edema in resistant hypertension studies. We know that aprocitentan's parent molecule's obviously got a low edema risk, but I wondered if you could talk about the similarities and differences from a pharmacological basis between aprocitentan and macitentan, maybe how its limited renal excretion and long half-life might further improve that edema profile relative to its parent molecule. That's the first question. Maybe I'll take them sequentially.
Okay. I think, Guy, you open up, and then we'll hand it over to Martine.
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 endothelin receptor antagonist, based on the many years of work that the Idorsia people have done in their previous company, Actelion. With aprocitentan in resistant hypertension, as is the case as well with macitentan in hypertension, essential hypertension, we didn't observe much of edema. I think the explanation is actually coming from the mechanism of action, and Martine is going to tell you why we have that very interesting observation.
Thank you, Guy. It's about 30 years of work, of research, where we have really tried to elucidate the role of the both receptors in pathological situations, and we have really understood that For chronic indications, it's important to block both receptors, but it's also giving a big difference. We have published preclinical data, which are explaining that when there is no blockade of both receptors, but only one, you have a potential relative activation, an imbalance which activates ETB receptors in different parts of the body and the kidney in particular. You have the risk of stimulating vasopressin and increasing vascular permeability, and that can cause edema. Therefore, we have put forward many years ago, the hypothesis was that with dual antagonist, we might have a low risk of edema. I think that over time, so far, that has been confirmed in clinical situations.
Right. We see on the safety slide that I showed, there are a couple of cases at the top doses. We didn't observe any weight increase in the trial compared to placebo.
It's not that we have zero, but in general, I think we have seen very
Right
very modest in number and in severity.
Okay, Richard, do you have some other questions?
Yes. I just wondered if there were 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, or just if there's any measures there. I mean, 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.
Right. Here, you're asking quite a lot of details on the protocol, which I may not have all in mind right now. 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. 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. Ideally, we would like to limit the flexibility in terms of the diuretic use, 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. 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? The second question on the trial is, do you plan to launch a long-term study looking at CV outcomes and maybe end organ protection? 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 50/50 shared with J&J. Maybe also if you can make a breakdown of that cost. As well, should we link this to the recent comments to seek new funding in 2019 to support large late-stage trials?
Okay, Guy, I think that's probably the last one, I think. Okay. I'll take the last one very quickly. On the cost description, you remember when we announced the in-licensing by J&J, where of the $230 million, $160 million were immediately revenue generating, while the remainder were deferred. That deferred part represents in rough what our cost could be if modeled. 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 break even, and those comments remain. Otherwise, Guy?
Right. On the second question, the long-term, of course, it's interesting scientifically and medically, it's not needed from a regulatory perspective. At the moment, what we do is to focus on developing a package that will be satisfactory to the regulators. 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. 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 two, and I can't remember what it was exactly.
Can the trial be stopped at the end of the part two?
Patients?
Can the trial be stopped at the end of part two instead of part three?
No. The part three 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. Of course, what will happen is that we start with many patients at the beginning, and some will not continue. Probably we have the dropouts as always in clinical trials, so there will be less patients entering into part three than part two and less part two than part one. The study is fully powered, and we calculated backward the sample size to be sure we had enough patients in part three. No, the study is not going to stop after part two. Actually, there is no reason to do so because the results of part one will not be known before the end of the trial.
There will be no basis for potentially stopping early.
Okay. Thank you very much.
Thank you, Vincent. 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 II, I wonder if you could detail what the two serious adverse events were on the 25 milligrams and whether either of those were cases of edema. Secondly, 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, is there any possibility in the trial protocol for patients who can't tolerate 25 milligrams in part two, who will obviously be titrated from placebo or the lower dose, to use the lower dose at all of aprocitentan? If patients can't tolerate the 25 higher dose, are they forced then to withdraw from the study at that point?
Sorry, just finally, is ischemic heart disease excluded from the study, given that there's a fixed dose that meets the standard protocol that's being used during the screening? Thank you.
Okay. I'm not sure I remember all the questions, taking the third one I think that you raised, which is the patient that do not tolerate during the part two. No, there will be no titration down. 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 our registration. There will be no possibility for patients to go back to either 12.5 or placebo. Long term is only 25. The first one, I must say that I don't have on the top of my head the detail of the serious adverse event. I should have put that as a footnote on the slide. That's clear. Thanks for asking.
I think it will be communicated in scientific communications at some point. I'm sure that was nothing of concern, but I can't remember what they were. I'm sorry for that. The second question, Andrew, if you can.
How many patients do we need to screen to get to the 600 patients roughly?
Yes. I will know that at some point in the trial when we see the screen fail rate. We have some estimates that probably we'll have to screen two to three times more, if not more, maybe up to even 10 times. Who knows? It's very difficult to know at this stage. We are ready to screen many, 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. We did the survey, we identified sites and patients in the sites up to more than 1,500 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.
In my view, counting on two to three 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 screen less because they're already very well characterized. That's one of the reasons why we did the SPIRIT survey to try to really identify the sites that can provide this population. Then we can minimize maybe the number of patient screens. We'd be a lot more comfortable to see that when we have a better view on the screen failure rate. The last one, question four, Andrew?
ischemic heart disease. Is that excluded, patients with ischemic heart disease?
Not completely, I believe. Actually, patients can, for example, receive in addition to the free 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. Chronic stable ischemic heart disease or ischemic events occurring much earlier than that would not be excluded entirely 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 there. 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. As I say very often, if I give you some timelines and we are actually much faster than that, I will be in trouble. I definitely don't want to take that risk. 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. 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 these sites in 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. 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.
I don't know 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, ethical committee approvals, and contracts we have to establish with the site and the institution. This can take quite a bit of time, and therefore, the secret for faster treatment is, number one, to pre-identify sites through activities like the survey we have done. Number two, 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. 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 II program.
Yeah. The phase II was done in hypertension, not in resistant hypertension. This one is done in a very well-characterized resistant hypertension. 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. Of course, the population is different.
Great. Thank you for taking my questions.
Thank you, Julian. Operator, next question, please.
The next question is a follow-up from Richard Parkes, Deutsche Bank. Your line is now open.
Hi. Thanks for taking my follow-ups. I've just got two or three. The first one's just on the clinical trial design. I think if I understand the trial design correctly, that you're only going to have placebo-controlled safety data 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, et cetera, more difficult to necessarily attribute to the drug versus the background patient population. 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.
Just interested around the choice between those two options and why you went for the automated in-office. Thank you.
Yeah. 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 first four 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 version of edema, which may of course become more complicated because some of the background medication are actually associated with edema, like amlodipine. Having said that, there was a comment made earlier by Martine and me about how we see edema, the risk of edema in this study. What we know as well from work that has been done with angiotensin antagonist is that if edema occur, they normally occur relatively quickly after treatment, and therefore, we would see that in the double blind part 1.
The choice of the instrument or the methodology for blood pressure, yes, we could do ambulatory blood pressure, or we could do ABPM. From our perception was regulatory wise, maybe ABPM was the best. This, I think is debatable, but in the end, both of them are being done. 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. We really don't expect that to occur. Both of them are going to be done. Just we prioritize automated office blood pressure measurement as a very reliable method and a standard, very easy to conduct a standardized methodology across all centers. No need to have complicated equipment on the patient body.
There are a number of reasons why we think it's a very reliable, easy to implement measure.
Okay, perfect. Just one final follow-up, just about further development of the compound. Obviously, there's multiple other possible indications, including diabetic nephropathy. 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.
Yeah, Richard. Further indications are options that Johnson & Johnson has. 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 [Sobey]. 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 aprocitentan 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 fourth drug? Or do you see aprocitentan being relegated more to the spironolactone refractory 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 these type of patients. It's really, this drug will be the first drug really studied and approved for this indication. 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 spironolactone. Especially that you see that today, a lot of diabetic patients are treated with SGLT2 type of compounds, which are diuretic also. Since all patients will be already under one diuretic, I think that the patients we are testing are not really the best candidate with spironolactone. I think that we really don't think that this compound or aprocitentan will compete with spironolactone.
Great. Thank you very much.
Thank you, Maria. Operator, next question, please.
There are currently no further questions. As a reminder, if you would like to ask a question, please press 01 on your telephone keypad now. I haven't received any further questions. I'll hand back to you, Andrew.
Thank you. If there are no more questions, I think we therefore come to the end of this update on aprocitentan. 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. Next scheduled event will be the first half results, expected on the 24th of July. Thank you for your continued interest and your support in Idorsia. Operators, please close down the lines.