Idorsia Ltd (IDIA) Earnings Call Transcript & Summary

Good afternoon, good morning, everyone. My name is Andrew Weiss. I'm the Head of Investor Relations and Corporate Communications here at Idorsia Pharmaceuticals. Welcome to our webcast to discuss the excellent results of the PRECISION trial Phase III study for aprocitentan in resistant hypertension, which we shared in a press release yesterday morning, European time. With me on the call are our CEO, Jean-Paul Clozel; our Chief Scientific Officer, Martine Clozel; and our Head of Global Clinical Development, joining us on the mic for the first time today, Alberto Gimona. A big welcome to you, Alberto.

Thank you.

Next slide, please. So as a gentle reminder, before handing over the mic, I need to make you aware that we will be making forward-looking statements. You, therefore, have been adequately warned about the risks and opportunities of investing in Idorsia shares. With that, I hand over to Jean-Paul for his introductory remarks. Next slide.

Thank you very much, Andrew. It's a great day today. And I think that I've been working since my first day in the pharmaceutical industry, which was in the 1990s, on hypertension. And at this time, it was not unfrequent to see younger women having stroke, young patients with renal failures. We had -- hypertension was a very significant problem. And thanks to the pharmaceutical industry and through the discovery of many antihypertensive drugs, this problem became less and less apparent. . But recently, and in the last 10 years, we have seen a very high number, again, of these young patients with uncontrolled high blood pressure having stroke. In fact, if you look at the numbers in the United States, a stroke in young woman becomes an epidemic. And we are seeing a lot of patients which cannot be controlled anymore for their high blood pressure. And this is why in Actelion and now with Idorsia, we have really started to really consider resistant hypertension as a very important clinical target. And you will hear why we decided to choose aprocitentan for a drug to tackle this problem. But then we went with this drug to the FDA to design the clinical program. And we went there with the classical program with 2 studies, 3 months endpoint and open-label phase. And the FDA told us, no, you can do something which should be more interesting. And this is the program we choose. And the program you will see is having 1 cohort of patients with 3 phases. And this program will be explained to you by Alberto Gimona. But this program especially had a withdrawal phase to confirm the long-term benefit of the drug. And you will see this program has been really fantastic. We were a little bit anxious, I have to tell you, because nobody has ever done such a program in the same cohort of patients, but the results we have seen are so clear, so consistent that, really, we can really thank the FDA for their very good suggestion. Unfortunately, today, I -- we cannot show you all the numbers or the quantifications of what we are going to describe since we want to keep this data for a publication and a presentation at very -- at an important Congress, and we need to preserve the publication. But I can tell you that after all this work, it has been really fantastic to be able to really see a drug which should help millions of patients today which have uncontrolled blood pressure, which are -- who are at a very high risk of a cardiovascular event. So I'll now let to Martine explain to you this very long journey towards finding such a drug. Please, Martine.

Thank you very much, Jean-Paul, and good morning, good afternoon to all of you. Next slide, please. I cannot tell you how happy I am today to be giving this presentation. The results we are discussing are the outcome of the research and a dream, which originated more than 30 years ago. That sounds like a long time, but it's a reality of how much effort it has taken for us to research on the endothelin system and to bring several endothelin receptor antagonists to maturity: two for the treatment of pulmonary hypertension, one for the prevention of digital ulceration for scleroderma, one for the prevention of cerebral vasospasm and subarachnoid hemorrhage, but now discuss today aprocitentan for resistant hypertension. I just want to say thank you to all my collaborators over the year and the exceptional team who have been involved in the discovery and development of aprocitentan. I would like to spend some time today now to map out our rationale for bringing aprocitentan. So first antihypertensive working pharmacological pathway in over 30 years to patients with resistant hypertension. Next slide, please. When endothelin was first described in 1988 as the most potent vasoconstrictor, we were, I believe, the only other group in the world working on its identification. The exciting discovery of endothelin continues to try to understand the system and its physiological and pathophysiological roles [ in falling ] regulating blood pressure was quickly established. And we published early on the finding of endothelin's likely role in hypertension. Soon, we also realize that endothelin was not only a vasoconstrictor, but rather a multifunctional peptide that could also drive cell proliferation, vascular hypertrophy, fibrosis and even inflammation, suppression of cytokines, catecholamine and aldosterone, thus potentially affecting fundamental pathological processing. The characterization of 2 endothelin receptors, ETA and ETB, 2 years after their first identification of endothelin gave us an additional challenge, understand the role of each receptor and identify which selective [ BP ] profile for endothelin receptor antagonist was the best and for which indication. Next slide, please. My team began working on understanding the endothelin system, its role in pathology and on the discovery of endothelin receptor antagonist with the goal of innovating endothelin. By 1993, we had described the first orally available ERA in Nature. And in total, after an intensive drug discovery program over the years, we described the discovery of 8 ERAs. We developed ERAs with different profiles, selective for 1 of the 2 endothelin receptors or dual antagonist. This allowed us to better understand the role of each receptor and what were the potential benefits of these tissues could be when intervening in the endothelin system. Next slide. This paved the way to the discovery of new treatments for cardiovascular diseases where endothelin was playing a role. The first evidence of a dual ERA in essential hypertension was published in the New England Journal of Medicine in 1998. In 2007, there was a failed attempt by another pharma company to take an ERA selective antagonist into the treatment of resistant hypertension, a logical indication with a very large unmet medical need. It has a much more severe prognosis and classical essential hypertension. Our own research focused on the development of aprocitentan for this indication. Next slide. So what is resistant hypertension and what do we understand about it? A number of effective treatments exist for essential hypertension, targeting a range of physiological systems. And yet, a subset of hypertension patients still suffer from uncontrolled high blood pressure despite the use in combination of optimal doses of several antihypertensive drugs of at least 3 different classes, including a diuretic. Next slide. There are known risk factors for resistant hypertension, which are shown here and include. Next slide, please, yes. Older age, particularly in women; high body mass index, obesity; ethnicity, with a higher prevalence in African American; obstructive sleep apnea. Many resistant hypertensive patients also have associated diabetes type 2 and renal insufficiency. Next slide. There are also known consequences of resistant hypertension. Patients who experience resistant hypertension are actually at much higher risk of endocrine damage as compared to those with classical essential hypertension that can be controlled. They have a much higher risk of cardiovascular morbidity and mortality by stroke, coronary heart disease, renal failure or heart failure. Please keep these 3 factors and [ end of game ] consequences in mind when we talk about the reason for aprocitentan in the treatment of resistant hypertension because all of these conditions, risk factors and consequences are associated with high endothelin status. Next slide, please. It is estimated based on the U.S. census that there will be almost 270 million adults in the U.S. in 2025. The division of Health and Nutrition Examination Survey estimates the prevalence of hypertension using the definition threshold levels at 130/80 millimeters of mercury to be around 45%, as published in Hypertension in 2019. Therefore, around 122 million people. Also in this survey, we can estimate a hypertension population receiving pharmacological treatment of 71.4% or 87 million people, as published also in Hypertension. Applying a resistant hypertension prevalence of 11.4%, we come to an estimate that around at least 10 million Americans are suffering from resistant hypertension with similar numbers in Europe. This means that there is well characterized and actually growing high number of people living with this so-called resistant hypertension, which is at high risk of serious consequences. Next slide. So why do we believe that the endothelin system is the right target to tackle resistant hypertension? Next slide. Firstly, endothelin was not targeted up to now by any of the current existing antihypertensive drugs. Therefore, when hypertension is resistant, it may be in [indiscernible] because it's dependent upon endothelin. Second, we have seen that certain populations when becoming hypertensive are at particular likelihood of having a hypertension which is resistant to existing antihypertensive drugs. Strikingly, all of these factors are present situations compatible with the role of endothelin, as we said. In addition, this is frequently associated -- diabetes, chronic heart failure or chronic kidney failure are also associated with increased ET-1. All of this suggests that resistant hypertension is actually an endothelin-dependent hypertension. Next slide. Indeed, this hypothesis fits perfectly with the pattern of resistant hypertension, which is often a salt-dependent hypertension. We know now that salt and endothelin are closely connected. And indeed, patients with resistant hypertension frequently have salt-sensitive hypertension, where blood pressure changes with changes in salt intake. Also, endothelin is likely to be involved in end-organ complications because we have seen the different effects which endothelin can have: aldosterone release, hypervolemia by increased salt in blood, vascular hypertrophy, fibrosis, inflammation and endothelial dysfunction. All of that means that the actions of endothelin fit perfectly the profile of a key mediator of resistant hypertension and its consequences. Next slide. With all of this evidence in mind, the use of the dual ERA to tackle resistant hypertension was the next logical step. Next slide, aprocitentan. Aprocitentan is a novel, oral, dual ERA that blocking both receptor, but potentially needed both endothelin receptor, high potency and both. It has a low potential for drug-drug interactions, which is important as resistant hypertensive patients have several comorbidities and are treated with [ critical ] medication. Aprocitentan demonstrated blood pressure decrease in animal models of hypertension and singularly models of salt-dependent hypertension. It demonstrated also a synergistic effect with blockers of the [ renal dysfunction ] system in animal models and renal and cardiac protection. After demonstrating an excellent safety profile and the blood pressure lowering effect in patients with uncontrolled hypertension, it was clear that aprocitentan was the ideal compound to take forward and develop for patients with resistant hypertension. The culmination of these evidence, combined with our confidence in the characteristics of aprocitentan, led us to PRECISION and the most challenging goal of demonstrating that aprocitentan to lower blood pressure in patients with resistant hypertension, where the existing standard of care has been in a decline. Our Head of Clinical Development, Alberto Gimona, will now describe the results of PRECISION and the very exciting positive results we are sharing and we shared yesterday. Alberto, the floor is yours. Next slide, please.

Thank you, Martine. Thank you, Jean-Paul. Actually, thank you, Andrew, for the welcoming at the beginning. Good morning, good afternoon, everybody. It's my pleasure to be presenting to you today in my new role as Head of Global Clinical Development at Idorsia. While I am new in this role, certainly for only for a few months, but I've been working with Idorsia for 3.5 years now. And actually, I know aprocitentan very well. I used to be at Actelion and have been working over 10 years in either company. Actually, I participated in person to the pre-IND meeting in 2014, if I'm not mistaken. And at the time, the community -- and actually, I must say also the regulatory authorities were doubtful that true resistant hypertension exist. Now with PRECISION, we show really that, that population exists. The clinical development of aprocitentan is a great example of what can be achieved with a great drug, a great team and actually an innovative, efficient study design, as Jean-Paul mentioned. We have heard the solid scientific rationale and properties of aprocitentan that actually make it suited, perfectly suited for resistant hypertension. Let's now take a look at the development program. Next slide, Slide 19. So our clinical pharmacology program confirm, among other things, that aprocitentan has a long half-life. And why this is important? Because it is important in treating hypertension and particularly resistant hypertension to cover the entire 24-hour period of a day for lowering blood pressure. It is particularly important also that in this polymedicated population, we have a drug, as Martine alluded to and that was confirmed in the clinical pharmacology, a very low DDI potential. So drugs used in this population do not have an impact and vice versa on their pharmacokinetic profile. On the middle, you see that our Phase II study demonstrated that aprocitentan reduce blood pressure in a dose-dependent manner and actually was instrumental in identifying the doses for Phase III. On top, you see the SPIRIT was a survey that helped us characterizing the resistant hypertension population what we should enroll. Now let's go to next slide, Slide 20. Here, you see the objective of the study. The primary objective of the study was to evaluate the antihypertensive efficacy of 2 doses, 12.5 and 25-milligram versus placebo. Secondary objective was to evaluate the durability of aprocitentan's effect over the long term, which is, as alluded by Jean-Paul, is a quite innovative feature of this program. Of course, it is very important for us to assess the safety over long-term 48 weeks, which will enable us to bring this new mechanism to a large patient population. Next slide, Slide 21. Now you see here depicted the study design. Again, in consultation with regulatory agencies, we arrived to the single international multicenter randomized study with 3 sequential treatment parts, preceded by a long screening and running in placebo running period. After the screening period, there was a Part 1 study of 4 weeks duration, at the beginning of which patients were randomized to placebo, 12.5 and 25 milligrams for 4 weeks. They were treated for 4 weeks. At 4 weeks, the primary endpoint, blood pressure, was measured according to an unattended automated office-based device. After 4 weeks, all patients, active and placebo, were switched to 25-milligram aprocitentan for the entire duration of the part B, which was 32 weeks. At week 36, at the end of the 32 Part 2, plus 4 weeks Part 1, the patients were rerandomized to 25 milligrams or placebo for the subsequent 12 weeks, bringing the total duration of the study to 48 weeks. One of the innovations of PRECISION, as alluded by Jean-Paul, is the withdrawal design. In fact, in Part 3 of the study, what we expect is that the patients who stay on aprocitentan, they maintain the low blood pressure that they achieved at the end of part 2, while the patients on placebo would deteriorate their blood pressure. Now let me briefly explain one of the critical feature of the study, the patient selections during screening and running. Next slide, please, Slide 22. As mentioned earlier, this was a rather long screening period, but this was needed to try to identify true resistant hypertension. And this is one of the paramount feature of PRECISION. There are several factors described in literature that make hypertension look like being resistant while it's not. There are some factors, and I would like to go briefly through them and see how we manage them so that we can neutralize. So hypertension could be secondary to a comorbidity. And this -- the protocol requested during the meeting -- the investigator during the screening period to exclude them. Sometimes, there are inaccurate readings of blood pressure, and we use an automated device with 5 ratings after a quiet period. And that is the white coat effect that, again, here, putting the patients in the room, in a quiet room, let them waiting few minutes before doing 5 measurements, reduce this white coat effect. Those measures were already introduced in some of other previous trials, obviously. But in PRECISION, we went a few steps further by avoiding, first, the inappropriate treatment regimen. One of the feature of the screening period that the patients background antihypertensive medications was standardized to guideline required treatment. Combination of calcium channel blocker, amlodipine, angiotensin receptor blocker, valsartan and a diuretic, hydrochlorothiazide for 4 weeks before entering a 4-week single-blind running. One and last reason that patients have not really hypertension is the poor treatment adherence. And therefore, we overcome that problem by providing the 3 background medication with 1 pill. We had eventually 1,965 patients. So 1,965 patients entering this screening period, with 730 coming up on it with hypertension demonstrated by systolic blood pressure over 140. Actually, it seems a lot of patients were failing. But indeed, actually, we expect more -- many more patients discontinue or screen fail during this treatment. We were targeting 4,000 patients to achieve the required number. And here, we saw only -- we needed only 2,000 patients that were needed to come up to the required number. If you are interested, I would encourage you to see, we are going to publish over the next few days, I believe, a very interesting paper describing all this process and the paper, Danaietash et al. in 2022. Now let's look at patient disposition. Next slide, Slide 23, okay? Of the 730 patients randomized in Part 1, we had an equal distribution across the 3 treatment group that can you see in the slide. And we had a discontinuation rate, which was low from 2.5% to 4.5% during the first week. You may notice that during the following period, Part 2, we have 30% discontinued rate. Overall, patient retention during the study was much better again than what we expected. We expected approximately 40% overall discontinuation based on the feedback that we have when you talk to the experts, the key opinion leaders and the investigators saying, it may be a bit difficult to keep patients on the study for 1 year. And actually, we only had about 20 -- overall 20% discontinuation, which in my opinion, suggests first and utmost that aprocitentan were well tolerated. Otherwise, the patients would not stay in the trial, was safe. And actually, also, in my opinion, shows that there is a population over there that I'm going to describe in a few seconds that needs treatment, and they are willing to participate to this study, which overall required 16 visits over 1 year. Next slide, please, Slide 24. Here, I would like to describe the population. Martine touched on that earlier on, and I see how this translates into PRECISION. Demographic characteristic is what you would expect in a population with resistant hypertension. You can see the age and sex distribution, nothing extraordinary there. I would like to point out a few things. 11% of the patients in the study were African Americans, but they represent the 1/3, 33%, of the patients enrolled in North America. So we actually had a good representation of the racial diversity in North America. And you see there that the patients have a relatively high BMI. On average, you see over 33, which qualify the people, unfortunately, for obese people. And of note, actually, we have 14%, 1 4, which were -- who were severely obese, with a BMI greater than 40. Finally, you can notice the blood pressure over 150 millimeters of mercury despite being on treatment. Next slide, Slide 25. On the top -- on the middle column, you see other very interesting characteristic of the population that we enrolled. As I mentioned just 2 seconds ago, they had a blood pressure over 150, systolic blood pressure. Now those patients are screening with 153 on average, where on 4 or 5 background therapies, antihypertensive therapies. So 62%, 63% of the population was, at screening, or 4 or 5 or even more actually, antihypertensive treatment before standardization. As I mentioned, very important the standardization. However, I would say also that we usually say that aprocitentan was given on top of at least 3. Now I can share with you that actually 60% of the patients in PRECISION were on 4 background antihypertensive treatment, the fourth being beta blockers, which were required not to be discontinued through the screening period. Another notable feature of this population was the high percentage of patients with chronic kidney disease, Stage III and IV, and we have here overall 22% of patients with CKD 3 and 4, so moderate to severe renal disease. This -- we were a bit puzzled by this because it's quite high and then maybe is due to the fact that we have many centers who are nephrologists. And also because the inclusion criteria of the study went down to an eGFR of 15 millimeters, while [ many ] in most studies go down to 25 only. Next slide, please, which is Slide 26, we give you the last picture of the population that I would like to share with you. This is really a highly comorbid population or, in lay terms, a very sick population. Over 50% of these patients had diabetes, 30% with ischemic heart disease, 23% even had stroke in their medical history and approximately 20% of patients had congestive heart failure. That is amazing. I hope I give you the idea of how this population was comorbid sick and how it was highly co-medicated. Next slide, Slide 27. Now PRECISION Part 1. In Part 1, 4 weeks duration, 730 patients randomized, 243, 243, 244, respectively, of 12.5, 25 and placebo. Next slide. And these are the results. I'm really happy to say that the primary endpoint was met. But I may have also said that I cannot share with you the numbers for the reason nicely given before by Jean-Paul. What I would say that after 4 weeks of treatment, a highly statistically significant and highly clinical meaningful reduction on systolic blood pressure was observed at both doses, 12.5 and 25 milligrams. Look at the p value, p is 0.005 versus placebo at both doses. Next slide, please, Slide 29. Following the 4 weeks double-blind placebo-controlled treatment, the patients entered the famous Part 2 or now the Part 2 is a single blind treatment period, all the patients are on 25 milligram. And actually, one of the interesting feature is that the placebo patients were switched to 25 milligram as well as 12.5 milligram switched to 25 milligrams. Next slide, Slide 30. Now in this part, there is no control group, so we have no statistics here. So we can look at the data. And what the data show is that the reduction in blood pressure, which was achieved at the end of Part 1, which was really nice, and I don't say anything more, was maintained for patients switching from 12.5 or continuing on 25 milligram. But maybe in this study, in this part of the study, the most interesting finding for me at least is that for those patients who switch from placebo, they rapidly went to the same level of blood pressure reduction observed in Part 1 with the active doses. So next slide, which is Slide 30. Now extremely important. And actually, earlier, Jean-Paul alluded that we were a bit anxious about that Part 3 of the withdrawal design, where the patients rerandomized to 25 and placebo, we needed to show an effect. Next slide, Slide 32. And great, we saw a wonderful effect also in this part of the study. In more rigorous terms, the key secondary endpoint was also met. The systolic blood pressure increased significantly on placebo compared to aprocitentan. Aprocitentan stay flat, actually reduced a bit. And in placebo, they quickly went back to what they had before. These results, as per discussion with the health authorities, show the effect of aprocitentan is maintained. And importantly, actually, this part of the study provides the required replication of efficacy as required by, namely, the FDA for regulatory submission. Next slide, Slide 33. Overall, we say that there is a consistent efficacy across multiple endpoints. Here you see on the left, the old endpoints related to blood pressure, automated office blood pressure, unattended systolic and diastolic. The 24 -- importantly, the 24-hour means systolic and diastolic blood pressure and probably even more clinically relevant, the night time means systolic blood pressure as measured with ABPM. There are consistent effect across all these parameters. And this is particularly important as the health authorities tell us, okay, you choose the primary endpoint, but what we really want to see is really a consistent effect. And we did observe a consistent effect. I mentioned the night time, very nice to see an effect there because it's predictive for long-term outcome. And actually, I don't say -- I didn't put in the slide here, but actually, we also have a consistent -- looking at all these parameters, we had a consistent effect across all the key subgroup of patients. Let's now -- next slide, Slide 34, go to the top line safety results. Generally well tolerated, no major safety concern in this patient population with both doses. Discontinuation from study treatment due to adverse event, you see there, the data in the slide was low. Treatment-emergent adverse event, adverse event during the first week double-blind period was reported by 26% -- 28%, 37% and in 12.5 and 25-milligram and 20% in placebo. And the most frequent adverse event was edema and fluid retention, as expected. Before getting a bit into the edema, fluid retention story, I would like to say that over the 48 weeks of the study, we didn't see any unexpected event, any additional event. And importantly, the MACE, the major adverse cardiovascular event, were within what we would expect in this population, highly comorbid population. Remember, the study was not designed to look at an effect of MACE because the major -- the majority of the time, the patients were on a single treatment arm. Let's go a second into the fluid retention story. We did observe 30% of patients who develop edema over the entire duration of the study. And at one time point during the study, it doesn't mean that the patient with edema stay with edema, actually the contrary. This incident should be viewed in relation to the 48-weeks duration and also the population. Remember, 22% CKD; 50%, Stage 3 and 4; diabetes, cardiac background medical history. And actually, I'm happy to see that 95% of these events were mild to moderate. We have only, overall, over 48 weeks, less than 1% actually, 2 cases of the serious adverse event. But actually, what is very meaningful to us and to the patients as a matter of fact, is that only 7 patients out of 730 patients discontinued due to edema and fluid retention. And this can be explained actually. We ask some of our investigators to say, well, we are used to it, actually. We have been dealing with amlodipine for years and decades, I would say. And amlodipine cause fluid retention, and we know how we can manage that. So I see that indeed over the 4 weeks, there is an imbalance across group, but the patients can and investigators can deal with that. That's why we say they're manageable. Now next slide, Slide 35, which are already my conclusions. I won't read the slide. But in a nutshell, I think we had a positive and clinically meaningful effect as shown over 4 weeks and maintained over long term. So the effect is durable. In relation to safety, I would add that actually, aprocitentan showed expected safety profile. And maybe since this is an ERA, although this is not for a long time now, not anymore a problem, but actually, I would like to just say that we didn't have any liver events, no highest case and basically no greater than 3x upper limit of normal for ALT/AST. On a summary note, I'm happy to see that the effect observed in Phase II as monotherapy in a younger and less comorbid population has been now confirmed as an add-on therapy in PRECISION in a relatively frail population. Again, sorry to come back, I'm like a broken record, but I think it is extremely important. This is a very sick population: 50% diabetes, 30% ischemic heart disease, 20% stroke, 20% -- a little bit less, congestive heart failure. This is a pain population which is on many different therapies. I haven't said that, but at the beginning, on top of the antihypertensive treatment that they have, they have, on average, 6 to 7 concomitant medication to treat their comorbidities. And here, as Martine said at the beginning, the low DDI potential of aprocitentan is certainly a plus in this case. Finally, the efficacy that I talked about that, the efficacy was demonstrated as add-on or at least 3 antihypertensive treatment, but actually, 60% of those patients were on 4 antihypertensive treatment. I cannot talk without thanking and having a big thank you to the investigators and the patients who took part of this study. Their great work has contributed to these results, these great results, and potentially, hopefully to the availability of the first new antihypertensive medicine actually passed through -- working through a new pathway for decades. Now I will hand over to Jean-Paul before opening the line to the questions. Next slide, Slide 36.

Thank you very much, Alberto. Really, it's a great set of results. I am really impressed by the results not only in efficacy, but of course, it's really efficacy in patients where we know that really no drug has been shown to work in this patient, in these resistant hypertension patients. But like always, the efficacy would be really not so relevant if the safety was not as good as we have seen because, really, we have seen mainly, I would say, leg edema as the main problem and nothing else. And as you know, when you are combining too many antihypertensive, you really might, and it has been happening in the past, you might see severe side effects, and I will not describe these cases. But really, it's always very difficult to combine antihypertensive drug without increasing tremendously the incidence of side effects. So I think we have a drug, which is really going to have a huge impact on public health, I think, because really resistant hypertension is a public health problem. Now we are going to really publish this data in the best journal we can. And of course, also publish the data in Congress. And before the end of the year, the NDA should be submitted to the FDA. And therefore, we are really on a good path to really have a new drug, which is going, once again, to change the life of many patients. So with that, I'd like to hand over to Andrew to open the Q&A session. Please, Andrew.

Thank you, Jean-Paul. So this concludes our prepared remarks, and we're now ready to open up the Q&A session. Please remember this is a clinical call, so please keep your questions to aprocitentan. If there are some questions on our relationship with J&J and the financing and the financial involvement, André will be joining us in the Q&A session. [Operator Instructions] Operator, please compose the roster.

[Operator Instructions] Your first question on the telephone comes from James Gordon from JPMorgan.

James Gordon, JPMorgan. My question was just how apro fits with Idorsia's longer-term outlook. So this is an asset where you've done the development as I understand it, but you don't have strategic control of the commercialization, so now it's derisked. Is it likely that you would look to divest all of the economics? Or is there a desire that you would retain ongoing economics with the product? And is the product sufficiently derisked that you could potentially divest your economic interest in it sort of imminently? Or is that something that could only really be thought of as further down the line? And if I could squeeze in just a follow-up one. Have you had a chance to talk with your partner J&J about the data? Has there been any comment from them on their level of excitement or any other comments coming from J&J about what they think of the product?

Thank you, James. I think the first part of the question we can give to André. That is exactly the reason why we have him on. And then for the excitement of J&J, I'll pass on to Jean-Paul.

Yes. Thank you, Andrew. James, it was more than one question there, but that's fine. Yes, we do not retain control of the asset. As you rightly know, J&J has opted in back in December 2017, paying an upfront of $230 million. They have also funded 50% of the cost sharing, around $120 million. So we're -- now have this asset, and we are entitled to tiered royalties between 20% and going up to 35%, depending on the annual sales level. So we do not retain control, but we have tiered interest in the success of aprocitentan. So to your second part of your question, do we contemplate to keep these royalties or sell it, for instance, a royalty monetization deal. This will mainly depend on the terms we could achieve for such a royalty monetization deal. But we won't because we strongly believe that this product has a huge potential in resistant hypertension, but also beyond in potential additional indication. We will definitely keep some of these royalties moving forward.

Jean-Paul, on the excitement?

Yes, I see. I think I will not put words in the mouth of Johnson & Johnson. I think they should. But I think the -- they have, of course, seen the data and we'll -- we have commenced -- we are really now in the new phase, which is the preparation of launch. So I think that this is now going on, and we will have many -- now many opportunities to interact with them. They need to digest the data because this has just been a few hours since they have been showing the data over a few days, I would say, since they have seen the data. But of course, there is a lot of also new analysis to be done. But I am very -- I think that they are -- I think they should be very happy.

Your next question comes from the line of Rajan Sharma from Deutsche Bank.

One on edema. And did you notice that rates were higher in any specific patient groups? For example, did it correlate with the number of background therapies a patient was on? Or was it linked to any of the comorbidities? And then just a second quick one. Do you anticipate the need for an ad com in the U.S.?

Alberto, I think you would want to take the question on edema.

Edema was, as mentioned, was observed in 30% of the patients. And actually, we are analyzing the data. I would -- as expected, I would say that in some specific population, you may see a higher incidence and some other lower incidence over time. But what I think it is, actually, you can see is an interesting feature because you see also edema -- and actually in up to 5% of the patients during the screening and running period. So this is a population, by itself, prone to have edema. So in a nutshell, there is nothing that is completely different in any of the sub group as far as the data that we have seen so far. You never know -- most importantly, all these events are manageable. Did I answer the question?

So Alberto, on the second part of the question, does anybody care to speculate on whether an ad com is needed?

No, we haven't had any discussion with the FDA. So we will usually -- we usually see after they receive the submission, which, again, we plan to do by the year-end. And after 2 months, we can say -- we can see whether they plan to have an ad com or not. So I would not speculate at this point.

Your next question comes from the line of Peter Welford from Jefferies.

[indiscernible]

Peter, we can barely hear you.

Sorry, can you hear me now?

Now we can.

Apologies. I've got just a couple of questions. I'll break the rules like everyone else, I'm afraid [indiscernible]. Firstly, can I just ask with regards to the study side, have you got confirmation from FDA that 730 patients, of which obviously not all were on drug, is sufficient for a regulatory filing and that you're not going to need any additional studies? I guess it looks like a relatively small safety database potentially for an indication of this size. And then just secondly, the emphasis has very much been on the U.S. in your presentation. Obviously, this is a global issue. Just to understand, is this commercially, given obviously this is a generically treated market, is this really commercially a U.S. opportunity we should focus on? Or do you think actually there's an opportunity to discuss with health regulators about this beyond the U.S.? And I guess, importantly, do you think you're going to need health outcomes, which I know this study doesn't provide, I don't think, to actually convince them of this, i.e., are you planning a large cardiovascular study, I guess? Or is there any data from this Phase III that you've done now that has health outcomes data that could potentially be used to convince both U.S., but more importantly, I think, your ex-U.S., but I guess both payers of the opportunity for this?

Thank you, Peter. I'll first pass them over to Alberto.

Okay.

Yes, go ahead.

Okay. For first question, one study, yes. We discussed with the FDA. And actually, they suggested the withdrawal design as a confirmatory. So we do not absolutely expect to do a second study before submission. And the safety database has been considered sufficient by the health authorities at this point. I cannot comment on the commercial beyond the U.S. But I would say that we are gearing up for the submission in other territories. And outcome data, I would say, okay, I cannot prevent future discussion about the next steps. But I think that the decrease that we observed in blood pressure is so meaningful that certainly can translate in labeling where we can see that by decreasing the blood pressure, we may have positive wording in the label as for many others, actually. So we don't -- I don't think for labeling, we need an outcome study.

Thank you, Alberto. Jean-Paul, do you want to add to the more strategic layer potentially on how the opportunity is for Europe as well with your view as a cardiologist and potentially where we could go with this compound in the future?

Yes. I just wanted to say -- to add on Alberto, that really hypertension is basically the only real surrogate blood pressure -- blood pressure is considered as a surrogate endpoint by the FDA. So they know that each millimeter of mercury, if you don't have a side effect, which is our case, particular side effect, of course, but with such a safety, we know that each millimeter of mercury is going to have a tremendous consequence on the outcome. And I would think even, I'm not sure it would be ethical to really do an outcome study after the results we have. So I don't think it would even be accepted by ethical committees because they know that blood pressure reduction means better outcome. And especially -- we have, of course, analyzed -- we are going to analyze, but we have already some very clear view on some very good predictors of outcome which can be measured in this patient. I will not go through. Let's keep a little bit of suspense for the presentation at the Congress. But there are some very good indications, which have been shown in the past to be very predictive of the future outcome of the patients. And this is also one of the reason why in Europe, there is a very big market. I think that the market is certainly as big, I would say, in Europe as in the U.S. I think that there is maybe less obesity issue, maybe less diabetes, but there are a lot of other risk factors, which are also present in Europe. It is also present in very many parts of the world. So I think that this drug should be really worldwide drug. And that, I'm quite convinced.

Your next question comes from the line of Dominic Lunn from Credit Suisse.

So I was wondering if you could speak a bit about your launch expectations. So you said, on average, there's around 6 to 7 concomitant medications. And we just note that when adding a branded drug to lots of other drugs, this is one of the reasons why ENTRESTO had a bit of a slow launch. So I just wanted to get your views on the launch expectations.

Thank you, Dominic. I think I'll be taking that one. So as you know, Johnson & Johnson is our commercial partner, and they will be responsible for the launch of the drug. So in terms of commercial expectations, I would want -- do not want to preempt any kind of comments on -- in that direction. Jean-Paul, would you want to add in terms of -- from a medical logic what potentially patients could be awaiting?

Yes, I think it's a very different case, ENTRESTO, our drug because basically, the ENTRESTO -- and I have to say, first, I hope we get the same success as ENTRESTO in the future because it's going to be a very -- it is already a very big drug, and I think it's going to be a very big drug. But also, ENTRESTO was launched in a market where there are several products, I would say, which can be used, for example, for heart failure. And here, we have a unique drug because it's a unique indication. Nobody has performed a study in the type of patient, nobody could show a benefit in the type of patients that we have tested. And I really think we are in a unique situation where there is no competitor. I always consider that before the potential competition would be from renal denervation. But I think that up to now, the studies have not been conclusive with renal denervation. And I do believe that having no whole drugs which can be taken so easily once a day is going to be -- and with such an effect and such a good safety is going to be a much easier way to deal with resistant hypertension and renal denervation. So we are not in such a competitive. And of course, all the generic will have been tested in these patients. So we are not competing -- or Johnson and -- Johnson & Johnson will not compete against generic because this is on top of all the generic products.

Thank you, Jean-Paul. We've come to the top of the hour. We're going to continue on with questions.

Your next question comes from the line of Thibault Boutherin from Morgan Stanley.

Thibault, we can't hear you.

Can you hear me?

Now we can.

Can you hear me? Okay, sorry about that.

No, it's gone. Your line is not working, Thibault. Okay. Operator, can we take the next question? Maybe he can jump back into the queue.

Your next question comes from the line of Peter Verdult from Citi.

Peter Verdult, Citi. One clarification, one question. Just on when we should expect to see the full data. Jean-Paul, I think you said an upcoming publication. If so, could you say which one and when are you targeting? Or should we -- do we need to be patient and wait for ESC or AHA? Just a clarification on when the market will see the data. Secondly, just my question, just wanted to double check there will be no disappointment when we see the headline efficacy data and what Idorsia considers to be faintly relevant chimes of what we get in terms of feedback from key opinion leaders. We know that the FDA requirement is just to show 5 millimeters, though docs tell us that, that in itself is [ not being irrelevant ]. Something approaching 10 or better is [ considered relevant ] and that's what you showed in Phase II. So I know you're not going to talk about the absolute numbers. But if you could characterize the data, that would be helpful. And it seems to me that you're alluding that the efficacy on the primary endpoint was equivalent between the 2 doses. Can you just clarify that in qualitative terms?

Thank you. Jean-Paul, do you want to care to speculate on the scientific publication?

Sorry. For the scientific publication, we are going to do it as soon as possible. And the first, I think the first should be in the Congress and a Medical Congress hopefully this year. Then it's always difficult to speculate because we look for the best journals, which are usually -- it's not a given. So I think that this data are so clear and so interesting that it should be in a really good paper. So I will not guess but we are going to -- we have already started to write this, to think of how we should and present this data. And of course, the investigators have also -- are going to be very interested to analyze this data. And maybe Alberto could comment on the -- what means a clinically meaningful effect for us.

Thank you, Jean-Paul. It's an easy question. I would say, actually, that we have a similar magnitude, what you can expect from this class of compound, which is effective in hypertension. And I would say that this is also on top of standard of therapy. So similar, same, similar magnitude of what is observed with other treatments, but are, for us, on top of 3 and 4. The second part of the question was...

No, that was all.

That was all?

The doses, the magnitude of effects on the prior [indiscernible].

The doses. Okay. That, I try to [ scotomize ]. We cannot comment on that again for the publication. So I would love doing that, but it would prevent us from publications. So I could not comment on that one.

Okay. Operator, do we have any more questions in the roster?

We currently have no further questions, sir.

Okay. I've got one question that came in on through the written channel. With regards to the recruitment criteria, how close would the recruitment criteria to the resistant hypertension definition in the guidelines when you compare those patient baselines?

So it's very consistent, actually. So I would say that there are no major differences. The difference here is that we excluded the -- with the patients who were not truly resistant. So as I mentioned in my presentation, we did make -- put a lot of efforts in making sure that the threshold that we observe here, over 140 milligrams -- millimeter of mercury of systolic blood pressure, was done despite the treatments and despite the placebo running period, despite the standardization and taking the background medication to the top. So I think this is -- if there is a study that is matching what is required by the guidelines, this is the one.

Excellent, Alberto. Thank you very much. So operator, have we had additional questions come in?

We have not, sir.

Thank you, Sharon. Okay. Well, therefore, we've come to the end of this conference call. I will thank all the participants for helping out all throughout the weekend and developing all of this material. We are very excited here with the results from the PRECISION trial with aprocitentan. As with that, I think we can conclude today's comment -- today's conference call. Operator, please close the line.