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 3 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. 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. At this time, it was not infrequent to see young women having stroke, young patients with renal failures. Hypertension was a very significant problems. Thanks to the pharmaceutical industry and to the discovery of many antihypertensive drugs, this problem became less and less apparent. 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 United States, stroke in young women becomes an epidemic.
We are seeing a lot of patients which cannot be controlled anymore for their high blood pressure. This is why in Actelion and now with Idorsia, we have really started to really consider resistant hypertension as a very important clinical target. You will hear why we decided to choose aprocitentan for a drug to tackle this problem. We went with this drug to the FDA to design the clinical program. We went there with a classical program with two studies, three months endpoint and open label phase. The FDA told us, "No, you can do something which should be more interesting." This is the program we choose, and the program you will see is having one cohort of patients with three phases.
This program will be explained to you by Alberto Gimona. This program especially had a withdrawal phase to confirm the long-term benefit of the drug. 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. The results we have seen are so clear, so consistent, that really we can thank the FDA for their very good suggestion. Unfortunately, today we cannot show you all the numbers of the quantifications of what we're going to describe since we want to keep this data for a publication and a presentation at the important congress. We need to preserve the publication.
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, who are at a very high risk of a cardiovascular event. I now let 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 ischemia for scleroderma, one for the prevention of cerebral vasospasm after subarachnoid hemorrhage, but now discuss today aprocitentan for resistant hypertension. I just want to say thank you to all my collaborators over the years. The exceptional team who has 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, the first antihypertensive working in a new 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 prompted us to try to understand the system and its physiological and pathophysiological roles. Its role in regulating blood pressure was quickly established, and we published early on the finding of endothelin's likely role in hypertension. Soon, we also realized that endothelin was not only a vasoconstrictor, but rather a multifunctional peptide that could also drive cell proliferation, vascular hypertrophy, fibrosis, and even inflammation, secretion of cytokines, catecholamine, and aldosterone, thus potentially affecting fundamental pathological processes.
The characterization of two endothelin receptors, ETA and ETB, two years after the first identification of endothelin, gave us an additional challenge. Understand the role of each receptor and identify which selectivity 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 antagonists with the goal of inhibiting endothelin. By 1993, we had described the first orally available ERA in Nature. In total, after an intensive drug discovery program over the years, we described the discovery of eight ERAs. We developed ERAs with different profiles, selective for one of the two endothelin receptors or dual antagonists.
This allowed us to better understand the role of each receptor and what were the potential benefits or safety issues 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 ETA-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 than classical essential hypertension. Our own research focused on the development of aprocitentan for this indication. Next slide. 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 three different classes, including a diuretic. Next slide. There are known risk factors for resistant hypertension, which are shown here and include older age, particularly in women, high body mass index, obesity, ethnicity, with a higher prevalence in African Americans, obstructive sleep apnea. Next slide, please. Yes. 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 end organ 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 risk factors and end organ consequences in mind when we talk about the reason for aprocitentan in the treatment of resistant hypertension, because all of these conditions, the risk factors and the 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 US in 2025. The National Health and Nutrition Examination Survey estimated the prevalence of hypertension using the definition systolic levels at 130/80 mm Hg to be around 45%, as published in Hypertension in 2019. Therefore, around 122 million people.
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. 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 part at least, because it's got
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. Well, I am new in this role, certainly only for a few months, but I've been working with Idorsia for three and a half years now, and actually I know aprocitentan very well. I used to be at Actelion and I've 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. At the time, the community and actually I must say also the regulatory authorities, were doubtful that true resistant hypertension exists. 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 19. Our clinical pharmacology program confirmed, among other things, that aprocitentan has a longer half-life. Why this is important? Because it is important in treating hypertension, in particular 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.
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 2 study demonstrated that aprocitentan reduced blood pressure in a dose-dependent manner, and actually was instrumental in defining the doses for phase 3. 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 20. Here you see the objective of the study. The primary objective of the study was to evaluate the antihypertensive efficacy of two doses, 12.5 and 25 mg versus placebo. Secondary objective was to evaluate the durability of aprocitentan's effect over long term, which is, as alluded by Jean-Paul, a quite innovative feature of this program.
Of course, it is very important for us to also assess the safety over long-term 48 weeks, which will enable us to bring this new mechanism to a large patient population. Next slide 21. Now you see here depicted the study design. Again, in consultation with regulatory agencies, we arrived at the single international multi-center randomized study with three sequential treatment parts, preceded by a long screening and run-in placebo run-in period. After the screening period, there was a part one study of 4 weeks duration, at the beginning of which patients were randomized to placebo 12.5 and 25 mg. 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 four 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 two plus four weeks part one, the patients were re-randomized to 25 milligram 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 three 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 two, 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 run-in. 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 is 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. Hypertension could be secondary to a comorbidity and this, the protocol requested that the investigator exclude them during the screening period. Sometimes there are inaccurate readings of blood pressure, and we use an automated device with five readings after a quiet period.
There is the white coat effect, and again, here, putting the patients in the room, in a quiet room, let them wait a few minutes before doing 5 measurements, reduces this white coat effect. Those measures were already introduced in some other previous trials, obviously. In PRECISION, we went a few steps farther by avoiding first an inappropriate treatment regimen. One of the features of the screening period is that the patients' background antihypertensive medications were standardized to guideline-recommended treatments: combination of calcium channel blocker, amlodipine, angiotensin receptor blocker, valsartan, and diuretic, hydrochlorothiazide, for 4 weeks before entering a 4-week single-blind run-in. One last reason that patients have not really hypertension is the poor treatment adherence. Therefore, we overcome that problem by providing the three background medications with one pill.
We had eventually 1,965 patients, so 1,965 patients entering the screening period, with 730 coming up on it with hypertension demonstrated by a systolic blood pressure over 140. Actually, it seems a lot of patients were failing, but indeed we expect more, many, many more patients discontinue or screen fail during this treatment. We were targeting 4,000 patients to achieve the required numbers, and here we saw only. We needed only 2,000 patients that were needed to come up to the required numbers. 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, all this process and the paper, Danai Bhatt et al. in 2022. Now, let's look at patient disposition.
Next slide. Slide 23. Okay. Of the 730 patients randomized in part one, we had an equal distribution across the three treatment groups, can be, that, can you see in the slide and we had a discontinuation rate, which was low from 2.5%-4.5% during the first week. You may notice that during this following period, part two, we have 30% discontinuation 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 expert, the key opinion leaders and the investigators saying, "it may be a bit difficult to keep patients on the study for one year." Actually, we only had about twenty overall 20% discontinuation, which in my opinion suggests first and utmost that aprocitentan was well-tolerated. Otherwise patients would not stay in the trial, was safe. 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 in overall required 16 visits over one 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 characteristics are what you would expect in a population with resistant hypertension. You can see the age and the 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 a third, 33% of the patients enrolled in North America. We actually had a good representation of the racial diversity in North America. You see there that the patients have a relatively high BMI on average, you see over 33, which qualifies the people, unfortunately, as obese people. Of note actually, we have 14%, one-fourth, 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 two seconds ago, they had a blood pressure over 150, systolic blood pressure. Now, those patients are screening with 153 on average were on 4 or 5 background therapies, antihypertensive therapies. So 62%, 63% of the population was at screening of 4 or 5 or even more actually, antihypertensives 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 three.
I can share with you that actually 60% of the patients in PRECISION were on four background antihypertensive treatments, the fourth being beta-blockers, which were required not to be discontinued during the screening period. Another notable feature of this population was the high percentage of patients with chronic kidney disease stage 3 and 4, and we have here overall 22% of patients with CKD 3 and 4. We saw moderate to severe renal disease. We were a bit puzzled by this because it's quite high and then maybe it's 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 mL/min, while, in most studies, go down to 25 only.
Next slide, please, which is slide 26, will give us 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 20, 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 was highly co-medicated. Next slide 27. Now, PRECISION Part 1. In Part 1, 4-week duration, 730 patients randomized. 243, 244 respectively on 12.5, 25, and placebo. Next slide. These are the results.
I'm really happy to say that the primary endpoint was met, but I'm also sad that I cannot share with you the numbers for the reason nicely given before by Jean-Paul. What I would say is that after four weeks of treatment, a highly statistically significant and highly clinically meaningful reduction in 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 four weeks double-blind placebo-controlled treatment, the patients entered the phase two. Now the phase two is a single-blind treatment period. All the patients are on 25 milligrams.
Actually, one of the interesting feature is that the placebo patients were switched to 25 mg, as well as 12.5 mg switched to 25 mg. Next slide 30. Now, in this part, there is no control group, so we have no statistics here. 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 mg. Maybe in this study, in this part of the study, the most interesting finding, for me at least, is that for those patients who switched from placebo, they rapidly went to the same level of blood pressure reduction observed in part 1 with the active doses.
Next slide, which is slide 30. Now, extremely important, actually earlier, Jean-Paul alluded that we were a bit anxious about the part three of the withdrawal design, where the patient re-randomized to 25 and placebo. We needed to show an effect. Next slide 32. 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 aprocentan. Aprocentan stay flat. Actually, it 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 that the effect of aprocentan is maintained.
Importantly, actually, this part of the study provides the required replication of the efficacy as required by namely the FDA for regulatory submission. Next 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, automatic office blood pressure, unattended systolic and diastolic. Importantly, the 24-hour mean systolic and diastolic blood pressure and probably even more clinically relevant, the nighttime mean systolic blood pressure as measured with the ABPM. There are consistent effect across all these parameters. 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." We did observe a consistent effect.
I mentioned the nighttime, very nice to see an effect there because it's predictive for long-term outcome. Actually, I said I didn't put in the slide here, but actually we also have a consistent effect looking at all these parameters across all the key subgroups of patients. Let's now go to the next slide 34, 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, and you see there the data in the slide, was low. Treatment-emerging adverse event. Adverse event during the first week double-blind period was reported by 28%, 37% in 12.5 and 25 milligram, and 20% in placebo.
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-week of the study, we didn't see any unexpected event, any additional events. Importantly, the MACE, the major adverse cardiovascular events, cardiovascular events, were within what we would expect in this population, highly comorbid population. Remember, the study was not designed to look at an effect on MACE because 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. Doesn't mean that the patient with edema stay with edema.
Actually, the contrary. This incident should be viewed in relation to the 40 weeks duration and also the population. Remember, 22% CKD, 50% stage three and four. Diabetes, cardiac background medical history. 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 a serious adverse event. 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. This can be explained actually, we ask, some of our investigators say, "Well, we are used to it, actually.
We have been dealing with amlodipine for years and decades, I would say, and amlodipine causes fluid retention, and we know how we can manage that. I see that. Indeed, over the four weeks, there is an imbalance across groups, but the patients can, and investigators can deal with that. That's why we say they're manageable. Now, next 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 four weeks and maintained over long term, so the effect is durable.
In relation to safety, I would add that, actually, aprocitentan shows the expected safety profile and maybe since this is an ERA, although this is not for a long time now, not anymore a problem. Actually, I would like to just say that we didn't have any liver events, no Hy's law case and, basically, no greater than 3 times upper limit of normal for ALT, AST. On a summary note, I'm happy to see that the effect observed in phase 2 as monotherapy in a younger and less comorbid population has been now confirmed as 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%, little bit less, congestive heart failure. This is a 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. Here, as Martine said, at the beginning, the low DDI potential of aprocitentan is certainly a plus in this case. Finally, the efficacy, but I already talked about that. The efficacy was demonstrated as add-on to at least 3 antihypertensive treatment. Actually, 60% of those patients were on 4 antihypertensive treatment. I cannot stop without thanking and giving a big thank you to the investigators and the patients who took part in this study.
Their work has contributed to these results, these great results and potentially, hopefully, to the availability of the first new anti-hypertensive medicine actually working through a new pathway in decades. Now, I will hand over to Jean-Paul before opening the line to the questions. Next 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, you know, it's really efficacy in patients where we know that really no drug has been shown to work in this resistant hypertension patients. 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. As you know, when you are combining so many antihypertensives, you really might and it has been happening in the past, you might see severe side effects.
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. 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 this data in Congress. Before the end of the year, the NDA should be submitted to the FDA. 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.
With that, I'd like to hand over to Andrew to open the Q&A session. Please, Andrew.
Thank you, Jean-Paul. 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. Please limit to one question and get back in the queue. Furthermore, there is also an opportunity to ask questions in a written form via the chat button. Operator, please compose the roster.
Thank you. Ladies and gentlemen, as a reminder, to ask a question via the telephone, you will need to press star one. To withdraw your question, press the pound or hash key. Once again, star one if you'd like to ask a question via the telephone. Your first question on the telephone comes from James Gordon from J.P. Morgan. Please go ahead. Your line is open.
Hello, James Gordon, J.P. Morgan. Thanks for taking the question. My question was just, how aprocitentan fits with Idorsia's longer-term outlook. This is an asset where you've done the development, as I understand it, but you don't have strategic control of the commercialization. Now it's de-risked. 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? Is the product sufficiently de-risked 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? 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. For the excitement of J&J, I'll pass on to Jean-Paul.
Yeah. Thank you, Andrew. James, it was more than one question there, but that's fine. Yes, we do not retain control over 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. They now have this asset, and we are entitled to tiered royalties between 20% and going up to 35%, depending on the annual sales level. We do not retain control, but we have a tiered interest in the success of aprocitentan.
To your second part of your question, do we contemplate to keep these royalties or sell it in, for instance, a royalty monetization deal? This will mainly depend on the terms we could achieve for such a royalty monetization deal. 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?
I think I will not put words in the mouth of Johnson & Johnson. I think they should, but I think they have, of course, seen the data, and we are really now in the new phase, which is the preparation of the launch. 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 shown this data. A few days, I would say, since they have seen the data. Of course there is a lot of also new analysis to be done. I am very. I think they should be very happy.
Thank you, Jean-Paul.
Thank you.
Thank you, James. Operator, next question, please.
Thank you. Your next question comes from the line of Rajan Sharma from Deutsche Bank. Please go ahead. Your line is open.
Hi. Thanks for the question. One on edema. 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? Then just a second quick one: Do you anticipate the need for an outcome in the US?
Alberto, I think you would wanna take the question on edema.
Edema, yeah, as mentioned, was observed in 30% of the patients. Actually, we are analyzing the data. As expected, I would say that in some specific population, you may see a higher incidence and some other lower incidence over time. Actually, you can see there is an interesting feature because you see also edema, and actually in up to 5% of the patients during the screening and the running period. This is a population by itself prone to have edema. In a nutshell, there is nothing that is completely different in any of the subgroup 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?
Alberto, on the second part of the question.
Outcome.
Does anybody care to speculate on whether an outcome is needed?
No, we haven't had any discussion with the FDA, so we would usually see after they receive the submission, which again, we plan to do by year-end. After two months, we can see whether they plan to have an outcome or not. I wouldn't speculate at this point.
Thank you, Alberto. Operator, next question, please.
Thank you. Your next question comes from the line of Peter Welford from Jefferies. Please go ahead. Your line is open.
Can I hear you?
Peter, we can barely hear you.
Sorry. You can hear me now?
Now we can.
Sorry. Apologies. I've got just a couple of questions. I'll break the rules like everyone else, I'm afraid, if allowed. Firstly, can I just ask with regards to the study size, 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 know, you're not gonna 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 generic treated market, is this really commercially a U.S. opportunity we should focus on?
Do you think actually there's an opportunity to discuss with health regulators about this and beyond the U.S.? I guess importantly, do you think you're gonna need health outcomes, which I know this study doesn't provide, I don't think, to actually convince them of this? i.e., you know, are you planning a large cardiovascular study, I guess? Is there any data from this phase 3 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 ex-U.S., but I guess both, payers of the opportunity for this? Thank you.
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. We do not absolutely expect us to do a second study before submission. The safety database has been considered as sufficient by the health authorities at this point. I cannot comment on the commercial beyond the U.S. I would say that we are gearing up for the submission in other territories. Outcome data, I would say, okay, I cannot prevent future discussion about the next steps.
I think that the decrease that we observe in blood pressure is so meaningful that certainly can translate in the labeling, where we can see that by decreasing the blood pressure, we may have positive wording in the label, as for many others actually. I don't think for labeling, we need an outcome study.
Yeah. Thank you, Alberto. Jean-Paul, do you wanna add to the more strategic layer potentially on, you know, how the opportunity is for Europe as well, you, with your view as a cardiologist and potentially where we could go with this compound in the future?
Yeah. I just wanted to say to add on Alberto that really hypertension is basically the only real surrogate.
Blood pressure is considered as a surrogate endpoint by the FDA. They know that each millimeter of mercury, if you don't have a side effect, which is our case, particular side effect, of course. With such a safety, we know that each millimeter of mercury is going to have a tremendous consequence on the outcome. I would think even I'm not sure it would be ethical to really do an outcome study after the results we have. I don't think it would even be accepted by ethical committees. Because they know that blood pressure reduction means better outcome. 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. There are some very good indications which have been shown in the past to be very predictive of the future outcome of the patients. 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 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. I think that this drug should be a really worldwide drug. That I'm quite convinced.
Thank you, Jean-Paul. Operator, next question, please.
Thank you. Your next question comes from the line of Dominic Lunn from Credit Suisse. Please go ahead. Your line is open.
Hi. Thank you. I was wondering if you could speak a bit about your launch expectations. You said on average, there's around 6-7 concomitant medications, and we just know that when adding a branded drug to lots of other drugs, this is one of the reasons why, you know, Entresto had a bit of a slow launch. I just wanted to get your views on the launch expectations. Thanks.
Thank you, Dominic. I think I'll be taking that one. As you know, Johnson & Johnson is our commercial partner. They will be responsible for the launch of the drug. In terms of commercial expectations, I do not wanna preempt any kind of comments in that direction. Jean-Paul, would you wanna add in terms of-
Yeah.
From a medical logic, what potential patients could be awaiting?
Yeah. 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 'cause 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. Here we have a unique drug because it's a unique indication. Nobody has performed a study in this type of patient. Nobody could show a benefit in the type of patient that we have tested.
I really think we are in a unique situation where there is no competitor. I always consider that the only potential competition would be from renal denervation. I think that up to now, the studies have not been conclusive with renal denervation. I do believe that having an oral drug 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 than renal denervation. We are not in such a competitive. Of course, all the generic will have been tested in this patient, so we are not competing with our Johnson & Johnson. 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 gonna continue on with questions. Operator?
Thank you. Your next question comes from the line of Thibault Boutherin from Morgan Stanley. Please go ahead. Your line is open.
Thibault, we can't hear you.
Hello, Thibault.
Hello, can you hear me? Now we can. Can you hear me? Yes. 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.
Of course, sir. Your next question comes from the line of Peter Verdult from Citi. Please go ahead. Your line is open.
Thank you. Peter at 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 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'll be no disappointment when we see the headline efficacy data and what the dossier considers to be clinically relevant chimes with 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 in itself is not clinically relevant.
Something approaching 10 or better is considered clinically relevant. That is what you showed in phase 2. I know you're not going to talk about the absolute numbers. If you could characterize the data, that would be helpful. It seems to me that you're alluding that the efficacy on the primary endpoint was equivalent between the two doses. Can you just clarify that, in qualitative terms? Thank you.
Thank you. Jean-Paul, do you wanna care to speculate on the scientific publication?
Sorry. For the scientific publications, we are going to do it as soon as possible. The first, I think, should be in the congress, in the 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. I think that this data are so clear and so interesting that it should be in a really good paper. I will not guess. We have already started to write this to think of how we should and present this data. Of course, the investigators are also going to be very interested to analyze this data.
Maybe Alberto could comment on what it means a clinically meaningful effect for us.
Right.
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. I would say that this is also on top of standard therapy. Similar magnitude of what is observed with other treatments, but for us on top of three and four. The second part of the question was?
No, that was all.
That was all?
The doses. The magnitude effect on the primary.
The doses. Okay. Yes, I try to systematize. We cannot comment on that again for the publication. I would love doing that, but it would prevent us from publication, so I could not comment on that one.
I can but try. Thank you very much.
Thank you, Peter. 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 were the recruitment criteria to the resistant hypertension definition in the guidelines when you compare those patients?
Yeah, yeah.
Baselines.
It's very consistent, actually. I would say that there's no major differences. The difference here that we excluded the patients who were not truly resistant. As I mentioned in my presentation, we did put a lot of efforts in making sure that the threshold that we observe here over 140 milligrams, you see, 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. I think that 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. 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 conference call. Operator, please close the line.