Idorsia Ltd (IDIA) Earnings Call Transcript & Summary

Dear, ladies and gentlemen, welcome to the conference call of Idorsia. As ordered from this request, this conference will be recorded. [Operator Instructions] May I now hand you over to Andrew Weiss, who will lead you through this conference. Please go ahead.

Thank you, Olie. Good morning, good afternoon, everyone, and welcome to today's Idorsia call on the launch of the Phase III trial for selatogrel and suspected AMI. Before I jump, I hand over the microphone to our participants. I do need to remind everybody that we will be making forward-looking statements in this call. So with me on the call today, Slide 3, please, are our CEO, Jean-Paul Clozel; our Chief Scientific Officer, Martine Clozel; and our Head of Global Clinical Development, Guy Braunstein. To make his introductory comments, I hand over to Jean-Paul. Thank you.

Thank you, Andrew. Thank you for the introduction. Next slide, please. So when we created Idorsia 4 years ago, we had very clear strategic priorities: number one, to deliver at least 3 products to the market in a short amount of time; number two, to build a world-class commercial organization; number three to bring Idorsia to sustainable profitability. And while we were doing that, we need to continue to fuel our pipeline with new discoveries, new drugs coming from our own research; and finally, to use the state-of-the-art technologies to drive innovation. Next slide, please. As I can show it on this slide, we really made very good progress for our pipeline. As you can see, daridorexant has been -- got the Phase III results. The drug has been -- the NDA has been filed, and we should get results at the -- we should get the approval at the beginning of next year. We also got very good results with clazosentan in Japan for subarachnoid hemorrhage, and we should have the results of lucerastat, another Phase III program, at the end of this year, aprocitentan in the middle of next year and cenerimod at the end of this year. So you see that we have a very -- we have made very good progress for our pipeline. And next slide. Today, I would like to speak of another Phase III program, which is going to start and which is addressing a very important clinical program. As you know, cardiovascular disease is the #1 cause of death before cancer in developed countries. In developed countries, 1/3 of the deaths are attributed to heart attack. 80% of the deaths caused by cardiovascular disease are due to heart attack or stroke. In the U.S. each year, 800,000 people get a new heart attack, and this is not only true for man, but it's also beginning to be a very significant problem in women. And each year, more than 3 million women have a heart attack worldwide. Next slide. In the previous slide, before joining the pharmaceutical industry, I used to treat the patients with cardiovascular problems. And there was always a very difficult question to answer. It was when the patient was asking me, can I go to holidays at this place? Can I sail? Can I have -- can I go on these cruise? Can I go on the top of this mountain or can I take a long flight? And it was very difficult for me to say, yes, because I knew that if this patient, who already had a heart attack, would have a new heart attack, why you were on this boat, where he was on this mountain. It would take him 4, 5, 6 hours to go to the first hospital to be treated. And that during this time, he could die. So most of the time, I will say, no, it's not prudent to do this long trip. So when one of our scientists, Sebastian who is also cardiologist, came with his idea to treat this patient at a very early stage. My first question was really, do we have the drug which would be able to treat the patients at the beginning of this -- of the heart attack as soon as they start to feel pain. And really, the first question, of course, was, do we have the drug to do that? And Martine is now going to tell you why selatogrel is indeed an ideal product to deal with this very significant clinical problem. Please, Martine. So next slide.

Thank you. Thank you very much, Jean-Paul. Good morning and good afternoon to all of you joining us today. It's my pleasure to share more information about yet another exciting discovery coming from our team. Slide 9, please. As many of you know, existing P2Y12 receptor antagonist are used in the treatment and prevention of arterial thrombotic event. Next slide. The clot has an established efficacy and a well-known safety profile with millions and millions of patients treated today. But despite the success of this class and other effective interventions, there remains a delisting unmet medical need in the treatment of AMI, next slide, which is a treatment during the time between the onset of symptoms and the recede of thrombotic treatment. Next, the study of AMI mortality shows that at least 20% of patients experiencing their first myocardial infarction died before reaching a hospital. And next slide, and approximately another 10% died during hospital admission. Slide 14. An antithrombotic treatment for use at the very onset of AMI symptoms would need to be rapidly absorbed and potent working quickly during this thrombus formation at a very early stage. The inhibition should be reversed after a few hours to avoid interfering with later treatment decision. And finally, it must have an appropriate safety profile for use prior to formal diagnosis of AMI. Testing the right P2Y12 receptor antagonist to be administered as close as possible to AMI symptoms onset presents an exciting opportunity to address this unmet needs and improve AMI outcome. Next slide. As Japan introduced, the scientists at Idorsia has developed a P2Y12 receptor antagonist called selatogrel. We believe selatogrel has the potential to provide the treatment benefit in addition to standard of care when administered at the onset of suspected AMI symptoms. I will now explain in the next couple of slides, the properties of selatogrel that support our trust and our excitement about its potential. Slide 16, please. Let's just look at why the onset of AMI symptom can be considered the actual optimal time to treat with P2Y12 receptor antagonist. Next, from the moment that symptoms start, everything goes very fast. Thrombus formation in one of the coronary arteries progress is an ischemia will rapidly cause irreversible damage to the heart. In the very initial stages of thrombus formation, the whole of platelets, in particular, platelet aggregation dominates, a process in which the P2Y12 receptor plays a key role. If left untreated, the thrombus will become fibrin rich and repeat on the slide progressively, fibrin -- fiber start to cover the platelets, which are adhering and aggregating and activated. And at that point, platelets will have a more limited role in thrombus formation. Next slide. This suggests that P2Y12 receptor antagonist could have a very important role to play in the initial stages of thrombus formation. Slide 19. Selatogrel has demonstrated properties that indicates that it has the potential to provide the treatment benefit in addition to standard of care, when administered at the onset of suspected AMI symptoms. Next slide. This drug has during preclinical and clinical development have shown that selatogrel is a potent and highly selective antagonist of the P2Y12 receptor, but in addition has a fast onset and a short duration of action. Next. Pharmacokinetic and pharmacodynamic studies shown selatogrel is rapidly taken up into the bloodstream following subcutaneous injection, next slide, demonstrating its fast onset of action. And on Slide 23, we can see that this study also shows that the effective antiplatelet activity of selatogrel is going down rapidly after its maximum and last for about 6 to 8 hours at the dose selected for further development, demonstrating selatogrel short duration of action. Slide 24. In pharmacology studies, preclinical data from a modified false model in genetics first suggested this property by demonstrating that thrombus formation was inhibited within 10 minutes of subcutaneous injection in the genetic of selatogrel. Next slide, we can see from this false model that following mechanical injury to such as carotid artery, a thrombus begins to form, resulting in repeated cycle, which you can see by the Doppler measurements of blood flow velocity translated into blood flow, resulting in repeated cycles of vessel occlusion, followed by dislodgement of the thrombus and reopening. Following subcutaneous injection of selatogrel, the occlusion dislodgement cycle continues for about 10 minutes, at which point, and you can see it in front of the white arrow, the blood flow is reserved up into the artery. Work in this model has also hinted that selatogrel may have the potential to dissolve an already found thrombus. Slide 27. In animal model of thrombosis and hemostasis, the dose providing antithrombotic effect, which was equivalent to that of ticagrelor, selatogrel resulted in a much lower level, a very low level of surgically induced blood loss. We later learned that this could be explained by selatogrel being highly selective for the P2Y12 receptor. Next slide. These properties, combined differentiate selatogrel from overall P2Y12 receptor antagonist, which has a slower onset of action, particularly during acute myocardial infarction and [indiscernible] and are selective for P2Y12 receptor. Slide 29. The properties are suggestive of a compound with the potential to provide a treatment benefit in addition to selatogrel was administered at the onset of suspected AMI symptom. Especially in addition, as a result of its solidity selatogrel is suitable for subcutaneous injection in humans. All of these factors helped our scientist thinking, how can we take advantage of the properties demonstrated by selatogrel to develop an effective treatment for use in the very early stages of AMI. Next slide. Because acute myocardial infarction is such an emergency because there is no time to await an ambulance and even less medical intervention in a hospital, one of our scientists, Sebastian had the idea of a self-administration by the patients at the onset of symptom. Self-administration is currently used to treat a number of other emergency situations, why not AMI. With that, I would like to hand over to Guy to tell you how we are going to assess whether this idea can become a life-changing innovation for patients. Guy, the floor is yours.

Thank you, Martine, and greetings to everyone following our presentation today. I think we should be on Slide 31 now. You have heard from Martine about the properties of selatogrel that gives us great confidence in our program. Now I would like to share with you the work that has gone so far to prepare the selatogrel Phase III registration study. Next slide, Slide 32. These diagrams schematically depict what happens today. Heart attack symptoms on the left of the slide can be sudden and intense and sometimes cause sudden death. However, in other instances, heart attacks are not painful or less painful that can start with the mild symptoms that develop gradually and symptoms are sometimes mistaken for less issues such as indigestion. Typically, patients will only take the symptom seriously when [indiscernible] and they then call the emergency service and make their way to hospital. The patients forget to recognize the symptoms and to take action results in the first aid of delay. Then depending on the speed of emergency response, there can be a further delay once the alarm has been raised. On average today, first medical contact can be delayed by up to 4 to 6 hours. Early intervention as quickly as possible on occurrence of symptoms suggestive of AMI is crucial to preserve the heart muscle damage. The longer the blood flow to the heart muscle is restricted, the more heart muscle damage will occur and the worst outcome for the patients, short-term and long term. Early interventional AMI has therefore, the potential to avoid the thrombotic process serve in heart muscle to improve long-term outcome and potentially saving lives. Next slide, Slide 33. An early intervention means here prior to first medical contact and decision being made by the patient, which implies a number of things. First, the symptoms have to be recognized by the patient. This means that patients have to be trained to recognize the different ways the heart attack presents and also to minimize the risk of diagnostic error. Second, to intervene means the product is safe and it is important to also minimize the safety risk in case no formal diagnostic is made and there may be diagnostic errors. The product has to act fast to optimize its efficacy in the short-term treatment window when the clock is still present as platelet rich and not yet fibrin rich as shown by Martine. Fast-acting means being effective within the few minutes. The treatment should be short acting, as also mentioned by Martine, to preserve standard-of-care upon medical contact. So that interaction with the procedure that will take place later when the patient reaches medical contact and also to minimize the risk of bleeding at that stage. The effects would therefore disappear in a few hours. Finally, if the patient has to administer the product themselves, it should be easy to use, and especially in the context of a highly stressed emergency context. Next slide, please, Slide 34. Let's look now at how we have addressed this prerequisite in preparing for our [ recreation ] stage. Next slide, Slide 35. This chart models the Phase I pharmacokinetic results presented by Martine a few minutes ago, on the left side. And the slide shows how the PK profile translates into inhibition of platelet aggregation on the right side. Our modeling shows that rapid IPA inhibition occurs at aggregation onset within 50 minutes. More than 90% of participants have more than 80% inhibition, 15 minutes after dosing. This strong inhibition of platelet aggregation lasts for approximately 6 to 8 hours. Having shown this to medicine people, it was also important to configure this PK and PD profiles obtaining individuals in patients and therefore, 2 Phase II studies in 2 different settings were established. Next slide, Slide 36. Our Phase II program evaluated the safety pharmacokinetics and pharmacodynamic characteristic of selatogrel in 2 groups of patients. The first group was in chronic coronary syndrome, that was a larger study, which allowed to give a safety database of a decent size. And the second study was done in acute myocardial infarction, it's a smaller study, but more relevant to the real-life situation of interest. Next slide, please. Slide 37. Most studies demonstrated significant inhibition of platelet aggregation. On the slide here, you see the inhibition of platelet aggregation on the vertical axis over time on the horizontal axis in patients with chronic coronary syndrome, of an injection of placebo, the triangle around symbol, 8-milligram selatogrel with pink dots or 16-milligram selatogrel with purple square. The subcutaneous administration of selatogrel 8- and 16-milligram induces a rapid platelet aggregation in addition with onset of action within 15 minutes and the height of its effect extend up to 4 to 8 hours depending on the dose. The Phase II study in patients with acute myocardial infarction showed similar results. These 2 studies confirm the efficacy profile we have seen in [indiscernible]. Slide 38. Next slide. Of course, safety is important, as I mentioned before. Treatment-emergent adverse events in clinical syndrome study suggest that selatogrel is safe and well tolerated. An excess of dyspnea was noted with both doses of selatogrel compared with placebo with most of the event being mild. This is a known adverse event from other reversible P2Y12 antagonist. Leading events were also observed in this study they were mostly trivial related to any function as part of the procedural intervention of the study and drowsing at the subcutaneous injection of the study drug. Importantly, there was no treatment [indiscernible]. Overall, the safety of selatogrel was good, and the drug was well tolerated. Next slide, please. Slide 39. So we see from the Phase II data, from the Phase II clinical development so far that we can seek 3 boxes you can say product fast-acting and short duration. Selatogrel uses profound platelet inhibition. It is fast-acting within 15 minutes of administration with appropriate duration. Selatogrel was well tolerated at both doses with no major [ bleeding ]. With this data, we selected [ 16-milligram ] at a dose for further investigation. As mentioned before, it's important also to have a convenient mode of administration. Next slide, please. Slide 40. Idorsia choose to work with a leader in the field of auto-injector to select and customize the right delivery system. Antares has a proven track record in developing drug-device combination products that are tailored to the therapeutic need and patient friendly. Together, we have developed a drug-device product combination, combining Idorsia selatogrel product with the Antares subcutaneous QuickShot auto-injector. Next slide, Slide 41. The Antares auto-injector was chosen for several reasons. First, its robustness. As it will be carried by patients in their bag or their pocket wherever they go, 24 hour a day, 7 days a week, 365 days a year. The product has to be available all time. Given the emergency use indication for the selatogrel drug device product, technical reliability for success through injection is a key criteria. Ease of use and emergency readiness are essential for patient, caregiver to handle device confidently during very stressful conditions. During the development of the device, Idorsia has conducted several manufactured studies, including a validation study in patient and caregivers of relevant age range in both sexes and in subjects with or without experience of self-injection. Next slide, Slide 42. The final validation study in the relevant population was conducted in situation, mirroring the real-life experience. The results of this study demonstrated that the auto-injector, the on label -- the on device label and the instruction for use allow the users to perform their task. Next slide, please. Slide 33. With these results, we can see another box here from the credit with this list, the easiness to use. Now to a very important criteria, symptom recognition. This is important to our concept because it needs the right product injected at the right time by patient that would be empowered to take actions. As a result, the patients must receive adequate training. Next slide, please. Slide 44. It is important that patients and their caregivers understand when and how to use the study auto-injector. The training material was developed with the educational experts, cardiologist, nurses, feedback from patients post-AMI on symptom recognition and when the patient have to inject on how to do it. How to use the study auto-injector and to call emergency services right after the injection. In the study, patients will also have to successfully practice a placebo injection prior to being randomized. Slide 45. With that said, we can now seek all the 5 boxes of all the prerequisites and we are ready to discuss the Phase III registration study. Next slide, please, Slide 46. With the study in the SOS-AMI, we will now put selatogrel in the hands of the patients. Next slide, Slide 47. The concept to be tested in the study is whether an early intervention, namely the self-injection of the P2Y12 antagonist selatogrel upon symptoms prior to formal diagnosis and medical contact leads to improved outcome. To do so, the SOS-AMI has been designed in collaboration with leading experts and has been discussed with health authorities. It is an international multi-center, double-blind randomized placebo-controlled parallel-group trial. In SOS-AMI, the patient is empowered to make self-decision at the very onset of suspected AMI symptoms. This empowerment requires engaging the patients in recognizing AMI symptoms and take immediate actions. Next slide, Slide 48. One of the key question is who will be enrolled in the study? Subject to be enrolled in the study within 4 weeks of a recent AMI either at high-risk of recurrent AMI. And patients are considered high risk if they had another myocardial infarction within the previous year or if they have several other factors such as diabetes, age over 65, active smokers and so on. Of course, prior to being randomized to study the patients, we will have to be trained and demonstrated that they can placebo inject themselves. This leaves us to the next slide, Slide 49, which is picked how the study will be operationalized. Here, you see a schematic of the study. Patients that had a recent AMI at high-risk of repeat heart attack will be enrolled in screening phase during which they will receive the training by the qualified trainers, including the practice of a placebo injection. They will then go for a 4-week -- within 4 weeks of the recent AMI into randomization in a one-to-one fashion to use of selatogrel and placebo. They then go about their normal life, carrying the auto-injector with them at all times. They will have regular telephone contacts with the trainers, which minimizes the burden of both patients and the study sites. When they experience and recognize any symptoms suggesting of an AMI, they will perform the require action, first, self-injection of selatogrel and immediately after call the emergency service to be taken to hospital. They will then be followed with post-treatment assessment for a month period. Next slide, Slide 50. We are planning to randomize 14,000 patients at approximately 250 sites in about 30 countries. A special protocol assessment has been agreed with the FDA. The FDA has also designated the investigation of selatogrel for the treatment of a suspected AMI in patients with a history of AMI as a fast track development program. The next slide shows the data flow. The primary objective -- Slide 51, the primary objective of the study is to assess the clinical efficacy of selatogrel when self-administered upon occurrence of symptoms suggestive of an AMI in patients at risk of having a recurrence. The success of this will be measured by the grading of AMI on a scale from no myocardial infarction after death. All events will be blindly adjudicated by Clinical Event Committee to ensure consistency across the many sites and countries around the world. Similarly, the primary set endpoint of bleeding will be blindly adjudicated by the Clinical Event Committee. So now Slide 52, coming back to what happens to AMI today. With selatogrel, we are addressing the delay between symptoms and treatment during which patients are most vulnerable. With selatogrel, we empower patients to take decision prior to [indiscernible] is the purpose of saving lives and improve long-term outcome. Slide 53. How could AMI be managing the future? As we see here, the self administration has the potential to change the life of the patient by slowing or stopping of the heart attack, early intervention leads to better odds short-term and long term. The key words to remember are safe administration of selatogrel using the auto-injector as early as possible at the onset of AMI symptoms by empower patients. It could change the treatment -- diagnose AMI. SOS-AMI is the next study on the selatogrel development, we look forward to reporting the outcome of SOS-AMI in approximately 2.5 to 3 years from now. And with that said, I will hand over to Andrew to open the Q&A session.

Thank you, Guy. So this concludes our prepared remarks. We've come to past the top of the hour. We have now at least 25 minutes to be able to address questions. Operator, may I ask you to open the lines for the Q&A session, please.

[Operator Instructions] The first question is from Peter Verdult, Citi.

It's Peter Verdult, Citi. A few questions from me, please. Firstly, just the anticipated cost of the Phase III program and anything you could say about the powering of the study? And then looking ahead, if this does become a success, is this a market you're looking to build yourself or would you seek a partner? And then related to that, just in terms of how this market gets built, what sort of KOL buy in have you got? Are there any significant heavy hitters that you've got on your advisory board or that you've got advocating and use of selatogrel in acute AMI? So I just wanted to get a sense of how much buying you've got from the key KOLs in the U.S. and Europe?

Okay, Peter. Thanks for that. That's a bull load of questions. Okay. So we've got: one, unanticipated costs; two, what are the powering assumptions of the trial. So beyond just what the patients are, but what we are expecting in terms of number of events that would be happening. In case of market success and we get the great data out there, when we do this on our own or with partner. And then fourthly, what are the KOLs thinking about this and how our interactions been with them. I will address quickly the cost one. I will refer the powering assumption one to Guy and then have the partnering and KOL by Jean-Paul. So the anticipated cost, regularly, we don't break down individual costs of the different trials. I think we've been able to indicate in the past so far that we don't think that the hosts will exceed those that we had for daridorexant as we develop that Phase III program, which took about 3.5 years from beginning to end. And it's been indicated in previous conference calls that, that would cost us somewhere around CHF 200 million to CHF 220 million and total over the whole lifespan of the Phase III program. Guy, do you want to address the powering assumptions of the trial, please?

Yes. I can take that question. So there are a number of components to this question. The first one is based on the rate of recurrence. Of course, this is based on analysis of databases that we have collected. And we know that not all patients are going to have reference within the observation period. The number two is also based on the probability that the patients will recognize and just in terms and decide to in fact and both of those are relatively unknown. And therefore, we make a number of assumptions of -- on these numbers to end up with a number of patients that have to be randomized, of 14,000. Now if you -- maybe your assumption is about the effect size or the size of -- the effect is going to better [indiscernible]. And we estimate that we may be able to reduce occurrence of events, it's a bit complicated here because we are -- we have a [indiscernible] by the endpoint. As I mentioned, in fixed level from no event to data. So therefore, it's not totally the same for all different levels. But overall, it's a 25% projection in the event wise on active compared to placebo.

Thank you, Guy. Jean-Paul, on partnerships.

Thank you, Andrew. So first thing is the first partnership is with Antares. I have to say Antares made a fantastic job to really come with us to the design -- to the adaptation of their device for selatogrel. We have a very good collaboration with Antares, and I'll take this opportunity to thank this very good company in the U.S. And this is important because I think the device and later on is its fabrication or its making is very important. That's the partnership that is very important for us. For the development, clearly, we are going to do it on our own. And frankly, if the study is positive, this drug and this combination will be prescribed by cardiologists. It will be a very specialized type of market. And therefore, we are thinking of selling it ourselves without a partner.

Thank you, Jean-Paul. Do you want to address the KOL community that is interested? And how we -- our interactions may have been with the FDA?

Yes. I think, first of all, the first community, which is important is the FDA. Because really, I can say and this was very clear at the time of the COVID because I did receive or we did receive a lot of inquiries of cardiologists, who wanted to have our device because, as you know, the number of patients in COVID crisis hospitalized because of myocardial infarction in New York was, for example, decreased by half, by 50%. People hesitate to go to the hospitals because of the, of course, contagious, but also they really were afraid to be contaminated. And therefore, it became a very significant problem. So it was very clear that this auto medication is very interesting. The FDA knows, especially in United States. And as you know, in the United States, it's very different to get the myocardial infarction if you are in the middle of New York or Boston or if you are in the middle of Oklahoma or Wisconsin. The time -- the chances to get to be treated is very different, and this is why the FDA thinks that this is a very useful tool. And that if it's really shown to work people very -- in very far remote location will have this auto-injectors at home and could treat themselves while they will be transported to sometimes the 7 or 8 hours travel to the first clinic. So it's -- the key opinion leaders, especially in the U.S., are very in favor. Of course, they want to see the results, but we had no problem to find centers interested into the study. And I have to say that both in Europe, in the U.S. and in the U.S., this concept is getting more and more traction and gets very big support from key opinion leaders.

The next question is from Graig Suvannavejh, Goldman Sachs.

Just a question on the trial design. So I know that a key element is to get patients to recognize the symptoms of a heart attack. How do you think you'll be able, from a clinical trial perspective to kind of normalize for that? And so I'm just wondering how this is going to actually play out and whether there is a certain element of variability that may confound the trial. So if you could address that, that would be great. And then I'll follow-up with the second question.

Yes. I can address the question. We have developed a training package, specifically with educators, patient educators, with physicians, with nurses and with patients that had myocardial infarction before. This package is being tested. This package is being translated into all the different languages in the different countries. And every country has a trainer and every trainer of the trainers, every site has a trainer and through this cascade of training trainers that will train the site trainers, we believe we'll be able to reach harmonization across the different sites and countries. As you have seen also from the graphical -- on the slide, the main contact for patients along the observational period is with the trainer. It will be done through phone calls. There will be reinduction regularly of the training done by these trainers on every site. So we have paid a lot of attention on the training. As you rightly point out, this is absolutely crucial to the study. It's crucial because we want the patient to recognize the symptoms, but the harmonization is also very important for the reasons you highlighted. And this is why we have put in place this way of training the patient, developing the master training program as well as recruiting the trainers in the different countries and the trainers at the site level that will work under the supervision of these country trainers.

And Guy, if I can add something because I suppose this was maybe part of the question is that about the confusing the results. If the patient does not recognize symptoms, which might happen, and we know it will happen, he will not inject himself. And therefore, he will not be included into the final analysis, which he is only taking care -- taking into account the patient who has injected themselves. And that's very important. This is why this type of -- is not a detail, this type of important element was agreed with the FDA because, of course, we didn't want to have patients who do not inject themselves, and were included into the study. I think it's important to know.

Maybe a quick follow-up to that. And then my second question, but the follow-up is, as it relates to those who inject themselves, and you just mentioned those are the ones that will be counted, but is there a consideration for the potential that perhaps you'll have subjects in the trial who inject themselves and actually are not having an actual AMI and perhaps as a false positive. Are they being accounted for in a particular way?

Sure. This can happen as well, of course. And so these patients -- as I mentioned, we have 6 categories and endpoints going from no event to that. So the patient that will inject when actually they have no myocardial infarction and maybe they are confusing the symptoms with something else will be counted as having none of the -- no infarction, no death. So they will be in that category #6. And this is accounted for in our sample set calculation, of course. It's, at the moment, of course, difficult to estimate how frequently this will happen. We are going to monitor that during the course of the study. But of course, this is a possibility, and this is accounted for in the said model.

Okay. And then my last question, and then maybe I'll jump back in the queue is with regards to your SPA that you have in place with the FDA, can you perhaps provide additional color as to what exactly is in that SPA? In other words, should we have a view that if you do hit on the primary endpoint that the FDA has agreed that it will approve the drug or is there some other element of the SPA that's important for us to keep in mind?

Yes. That's, in general, the interpretation of SPA. The SPA agreement means that if we conduct the study and we connect it well, this is an important component as well. And the study delivers the results that are expected, the likelihood of approval is very, very high. It's never 100% commitment, as you know, with agencies. There are always things that can happen that may lead to different decisions. But it gives us a very good comfort in respect to the potential for being approved, assuming that the study is well conducted and the results are aligned to what we expect.

And the next question is from Rajan Sharma with Deutsche Bank.

First one, could you just give us a sense of how many patients at present experience a second event within 12 months? And then on that point, just thinking about market sizing, do you have a sense at the minute of how successful patients are in successfully identifying an AMI? So for example, do you have any data to tell us how many patients when they experience symptoms actually contact emergency services?

Yes. I will not give you exact numbers, but estimate because, of course, the study has not started yet, and these estimates are going to be revised as the study is going on. But overall, we anticipate that approximately 1/3 of the patients will recognize the symptoms and self inject. This is just a rough estimate at the moment. That's what we anticipate. It may be a bit less. It may be a bit more, but it's approximately that. And that's why we need such a large study because the majority will probably not have symptoms within this period of observation.

Okay. And then maybe if I could just follow-up with a quick one. Just in terms of going back to the commercialization, what do you think, going back to your comments that it being a specialized niche indication, what do you think is the right size for a commercial organization? What kind of infrastructure would you need?

Okay. Jean-Paul, do you want to address? How large do you think the heart attack survivor patient actually is?

I think that there is a very big mistake is always to address the market size and to confuse the market size with the recruitment criteria. If I take the example of pulmonary hypertension. When we did a study in pulmonary hypertension, we did a study in patients with a certain amount of limitation in all distance, but it has never been in our label something which was required to treat for patients with pulmonary hypertension. But it was something which was allowed to characterize the patient during the study and to be sure that we were treating a patient, which was sick was also giving us a chance to get a positive response. This is the case with our study. In fact, what we want to show is that when you have a myocardial -- an initial myocardial infarction, and you treat the patients with our auto-injectors, it will save him maybe in a very large amount of time. We don't -- we say at least 30%. It will save him from myocardial infarction. If it was his first myocardial infarction, it might be the same, but it would be impossible to do a study or it would be very, very time-consuming and very difficult, we will need maybe 50,000 or 60,000 patients. If we would do a study, for example, in patients at risk of acute myocardial infarction, and we never had myocardial infarction also would not be able to recognize as well the myocardial infarction. But it doesn't mean at all that the FDA is going to limit our indication exactly to the criteria of inclusion in our study. That's the number one. Therefore, the market is really clearly not only the patients who got a myocardial infarction 1 year before because if they got in 2 years, the risk of a new myocardial infarction is lower, but it is still there. If they got 3 years before myocardial infarction and they have diabetes, they still have a high-risk of myocardial infarction. So depending on the results, depending on the extent of the effect, the market is going to be much more -- much larger than patients who got in the year before or in the month before myocardial infarction. This is really something that people have to keep in mind. And then if the study is positive, of course, the size of the marketing is really addressing the cardiologist of the United States because I really believe that only cardiologists would prescribe such a drug and I think it's quite a limited market. It's a limited size of medical representatives. And I do believe that it will be very, very difficult for a patient who is known to be at risk, not to carry such a device because it's really -- if it's positive, our study is positive, it could really save his life. So I think that the adherent, like for the [ epi PAD ] was a huge success because it's influence into safely for the patients to carry something because today, imagine to get the myocardial infarction on the Gulf Coast or in the middle of nowhere, it's quite terrible because you have to wait very often for a long time. So I think that cardiologists will prescribe it, and it will be limited cost of marketing.

Thank you, Jean-Paul, for those clear statements. Operator, do we have any other questions?

Yes. We do have a final question from Barbora Blaha, Crédit Suisse.

First one, maybe I missed it, but how long do you think will this study take, this observational phase?

Right. We are planning an observation phase of approximately 1 year. It may be a bit longer. We don't know at the moment, we are planning. And therefore, as I mentioned in my presentation, we should see the results in approximately 2.5 years time to select the study. Hopefully the subject to train them and to observe them, we take that longer.

Okay. And then another question. I don't really understand why you have a 6-point scale in this efficacy assessment? What are the other points? And could you maybe explain this a little bit?

I'm sorry, I didn't catch the details of your question.

So I don't really know why you have this 6-point scale of your efficacy assessment.

Yes. So basically, the worst-case that the patients will die. The best case is that there will be nothing. And in between, we have several levels, non-semi and semi, and we have also different levels of [indiscernible] within the 2 categories. So in total, it's 6 levels. It's important because we cannot do a survival study that is relatively infrequent. And therefore, we also want to look at semi and non semi. And we also have an interest in the long-term outcome of the patient and the long term outcome, of course, is also driven by those that will survive the acute events and may be develop heart failure due to the repetition of myocardial infarction.

But the most important is the death or MAI for the success of the study?

They are all very important because they all contribute to the -- that ratio. It's not exactly in that ratio, but it's fills up on that ratio. So they all contribute, and we have an anticipation that all of them -- all of the categories will have a reduction on selatogrel, except the category where there is no event also. There will be an increase on selatogrel compared to placebo. And they all contribute to the said outcome based on the outcomes from today.

And then just something last, if there is no event, this can be either people who had no symptoms at all, but falsely injected themselves as well as people who had symptoms and then injected selatogrel and selatogrel helped to decrease this event?

Yes. And this is possible. It would be quite remarkable if this becomes the main issue. And also that if they had an ischemic event, there is no biological twice of that, for example, increasing [indiscernible] but there is a possibility that if the event is aborted very quickly, may be consumed by those that injected for the wrong reasons. The blinded adjudication by the independent committee will certainly help us in that effect.

And I would like -- I think it's -- your question is very good. I just would like to complete and Guy, you can correct me if I am wrong, please. But I think that your question, it was -- it's an important question because it was really also the suggestion of the FDA about this continuity within the endpoint. I think they were really much in favor. This was discussed in the FDA. This is a very important element because what can happen is that a patient who would have died without auto-injector now can survive. So the number of deaths can increase, but if he would have had a mild infarction, then he can have a much milder infarction. So if he would have I would say, an infarction with clinical signs, now he can have an infarction with only enzyme increase without clinical sign, and every of these steps is an improvement for the patient. And we wanted to capture all possible improvement for the patients, which are, I think, relevant, and this is why we made the 6 steps, which I think is a very elegant way to capture all the potential benefits because as you know today, there is a very important clinical use of measurement of enzyme in the plasma and therefore, we really wanted to know if -- if we would, for example, have in addition to this enzyme clinical sign and other elements to characterize the extent of the myocardial events. And this was asked by the FDA. And this was, I think, and we completely agree, this is the best way, in my mind, to assess the effect of this auto injector.

Thanks, Barbora. Thanks, Guy for those remarks. Operator, are there any questions left?

Yes, we do have a question from Mark Panera, Jefferies.

Just a quick one. I'm not sure it's been asked, answered or not, I might have missed it. But if a patient in the study does have an AMI event and regardless whether I would say a mischaracterization or not, do they receive -- and if they use a pen, do they receive another pen and continue on in the study for the duration or not?

Guy, do you want to address that?

Yes. Once patients are allowed to self-inject several times during the course of the study, exactly as you described it, whether they have actually a first event or not as a matter, if they use the pen to inject, they will get a receipt -- they will get a new pen, and they can, again, be followed and potentially inject at another time. Absolutely.

Thank you, Mark. Operator, any questions?

No further questions at this point.

Thank you very much. So we've come to the full hour of this conference call, including the question-and-answer session, I think we'll call it a day for today. Thank you very much for your attentive questions and your follow-ups. This is a very exciting moment for us and a very exciting compound. So on that note, we'll close the call for today. Our next prepared remarks are going to be with the half year results on the 27th of July. And until then, I wish you well. Take care, everybody. Thank you. Operator, close down the lines.

Ladies and gentlemen, thank you for your attendance. This call has been concluded. You may disconnect.