Study Update

Jun 28, 2021

Dear, ladies and gentlemen, welcome to the conference call of Eudoxia. At our customer's request, this conference will be recorded. As a reminder, all participants will be in a listen only mode. After the presentation, there will be an opportunity to ask questions. May I now hand you over to Andrew White, who will lead you through this conference. Please go ahead. Thank you, Aurelie. Good morning, good afternoon, everyone, and welcome to today's DYORSA call on the launch of the Phase 3 trial For selapsogrel 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 Clozell Our Chief Scientific Officer, Martin Clozell and our Head of Global Clinical Development, Guy Brownstein. To 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 the Diodorusia 4 years ago, we had Very clear strategic priorities. Number 1, to deliver at least 3 products to the market in a short Number 2, to build a world class commercial organization Number 3, to bring hydrocia to sustainable profitability. And while we were doing that, we 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, the Redirection As 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 approval at the beginning of next year. We also got very good results with Clazozantin in Japan for Subiac nor hemorrhage. And we should have the results of Lucerastat, another Phase III program, at the end of this year, Aprositenta in the middle of next year and scenario mode at the end of this year. So you see that we have 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 number one cause of death before cancer in developed countries. In developed countries, 1 third 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 the True for men, but it's also beginning to be a very significant program in women. And each year, More than 3,000,000 women have a heart attack worldwide. Next slide. In the previous slide, before joining the pharmaceutical industry, I used to treat the patient 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 this 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 while he was on this boat, while he was on this mountain. It would take him 4, 5, Cyrus to go to the 1st 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, Sebastien Roo, who is also a cardiologist, they came With this idea to treat these patients at a very early stage, my first question was really do we have the drug Which will be able to treat the patients at the beginning of this of their 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 Martin is now going to tell you why selatobrell is indeed an ideal product To deal with this very significant clinical problem, please, Martin. So next slide. Thank you. Thank you very much, Jean Paul. Good morning or good afternoon to all of you joining us today. It's my pleasure to share more information about Yes, another exciting discovery coming from our team. Slide 9, please. As many of you know, existing P2Y12 receptor antagonists are used in the treatment and prevention of arterial thrombotic events. Next slide. The cloud 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 distinct Unmet medical needs in the treatment of AMI, next slide, which is a treatment during the time between the onset of symptoms and the receipt of first anti thrombotic treatment. Next, a study of AMI mortality showed that At least 20% of patients experiencing their 1st neo cardial infection died before reaching a hospital. And next slide. And approximately another 10% died during hospital admission. Slide 14. An autothrobotics treatment for you at the very onset of The AMI symptoms would need to be rapidly absorbed and potent, working quickly to inhibit conversion at a very early stage. The inhibition should be reversed after a few hours to avoid interfering with later treatment decisions. And finally, It must have an appropriate safety profile for use prior to formal diagnosis of AMI. Testing the right T2Y12 receptor on Telenis to be administered as close as possible to AMI since on sunset We'll present an exciting opportunity to address these unmet needs and improve AMI outcomes. Next slide. As Jean Paul introduced, the scientists at Hydoxia have developed a P2Y12 We believe Selatocyan has the potential to provide the treatment benefit in addition to standard of care When admitted, start at the onset of suspected BMI 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 first look at why the onset of AMI symptom can be considered the actual optimal time to treat with a Next, from the moment that TimTom starts, Everything goes very fast. From this formation in 1 of the coronary artery, progresses And ischemia will rapidly cause irreversible damage to the heart. In the very initial stages of thrombus formation, The role of platelets, in particular platelet aggregation, dominates a process in which the P2Y12 receptor plays a key role. If left untreated, the TRONDYS will become fibrin rich, and we see it on the slide. Progressively, fiber starts to cover the platelets, which are adhering and aggregating and activated. And at that point, platelets will have a more limited role in progress formation. Next slide. This suggests that P2Y12 receptor antagonist could have a very important role to play in the initial stages of strongest formation. Slide 19. Telazopril 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. Data gathered during preclinical and clinical development Have shown that selatozrel is a potent and highly selective antagonist of the P2Y12 accessor, but in addition has a fast onset and a short duration of action. Next, pharmacokinetic and pharmacodynamics studies And shown, selatol is rapidly taken up into the bloodstream following subcutaneous injection. Next slide. Demonstrating its fact onset of action and on Slide 23, We can see that these studies also show that the effective antiplatelet activity of selazotrel is going down rapidly Slide 24. In pharmacology studies, Preclinical data from a modified false model in Genoptix first suggested this property By demonstrating that tremendous formation was inhibited within 10 minutes of subcutaneous injection In the guinea pig of Selakon. Next slide. We can see from this false model That following mechanical injury to, in that case, carotid artery, a Tremblece begins to form, resulting in repeated cycle, which you can see here by the Doppler measurements of blood flow velocity translated into blood flow, resulting in repeated cycles of vessel occlusion followed by dislodgement of the fungus and reopening. Following subcutaneous injection of selatocell, 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 restored into the arteries. Work in this model has also hinted that Selatergaly may have the potential to dissolve an already found from this. Slide 27. In animal models of thrombosis and hemostasis that the dose providing on thrombotic effect, which was equivalent to that of ticagrela, 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 selatovel being highly selective for the P2OI12 receptor. Next slide. These properties combined differentiates Elatopel from overall P2Y12 receptor antagonist, which have a slower onset of action, particularly during acute near guardian infarction and 30 for longer and are less selective for the P2I12A sector. Slide 29. The properties are suggestive of a compound with the potential to provide the treatment benefit in addition to standard of care when administered at the onset of suspected EMI symptoms. Crucially, in addition, as a result of its solubility, Telatopel is suitable for subcutaneous injection in humans. All of these factors held our scientists' thinking how can we take advantage of the properties demonstrated by Telazotide to develop an effective treatment for use in the very early stages of ANI. 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. 1 of our scientists, Sebastien, had the idea of a self administration by the patient at the onset of symptoms. Health 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. Yi, the floor is beyond. Thank you, Martin, and greetings to everyone following our presentation today. I think we should be on Slide 31 now. You have heard from Martin about the properties of Selatoglaide 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 selatovel Phase 3 oral discussion 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, but can start with mild symptoms that develop gradually And symptoms are sometimes mistaken for less serious issues such as indigestion. Typically, patients will only take the symptoms seriously And they then call the emergency service and make their way to the hospital. The patient's failure to recognize the symptoms and to take action Results in the first bit 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, 1st medical contact can be delayed by up to 4 to 6 hours. Early intervention as quickly as possible Occurrence of symptoms suggestive of AMI is crucial to prevent the heart muscle damage. The longer the blood flow to the heart muscle is restricted, The more heart muscle damage will occur and the worse the outcome for the patients short term and long term. Early intervention and AMI are therefore the potential to avoid the thrombotic process, saving heart muscle to improve long term outcome and potentially saving lives. Next slide, Slide 33. An early intervention means Here, prior to 1st 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 are to be trained to recognize the different ways the heart attack presents and also to minimize the risk of diagnostic errors. 2nd, to intervene with the product that is safe and it is important to also Minimize the safety risk in case no formal diagnostic is made and there may be diagnostic error. The product has to act fast To optimize its efficacy in the short term treatment window when the clock is present at a plateau reach And not yet fibrin, which as shown by Martin. Fast acting means being effective within a few minutes. The treatment should be short acting, as also mentioned by Martin, to preserve standard of care upon medical contact, to avoid interaction with the procedure that will Later when the patient reaches medical contact and also to minimize the risk of bleeding at that stage. The effect should therefore disappear in a few hours. Finally, if the patient has to administer the product themselves, it should be easy to use, especially in the context of highly stressed Emergency context. Next slide please, Slide 34. Let's look now That's how we have addressed these prerequisites in preparing for our registration study. Next slide, Slide 35. This chart models the Phase 1 pharmacokinetic results presented by A few minutes ago, on the left side, and the slide shows how the PK profile translates into Inhibition of blood test aggregation on the right side. Our modeling shows that rapid IP inhibition of blood test aggregation onset within 15 minutes. More than 90% of participants have more than 80% inhibition 15 minutes after dosing. The strong inhibition of platelet aggregation lasts for approximately 6 to 8 hours. Having shown this in LC people, it was also important to confirm this PK and PD profiles of Telenas individuals in patients And therefore, 2 Phase 2 studies in 2 different settings were established. Next slide, Slide 36. Our Phase 2 program evaluated the safety, pharmacokinetics and pharmacodynamic characteristics 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 different size. And the second study was done in acute myocarditis fraction. It's a smaller study, but more relevant to the real life situation of interest. Next slide please, Slide 37. Vostaleza demonstrated significant inhibition of bloodlet 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. Upon injection of placebo, the triangle or orange symbol, 8 milligram selatograde, the pink dots, or 16 milligram selatograde, the purple square. The cyclotenus administration of selatoveril 8 16 milligram induces a rapid platelet aggregation inhibition With onset of action within 15 minutes and the height of its effect extend over 4 to 8 hours depending on the dose. The Phase 2 study in patients with acute macular infarction showed similar results. These two studies confirm The efficacy profile we have seen in Mercy volunteers. Slide 38, next slide. Of course, safety is important. As I mentioned before, treatment emergent adverse events in chronic coronary syndromes studies suggest that selatoGryl is safe and well tolerated. An excess of dyspnea was noted with both doses of selatogaly 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 venipuncture as part of the procedural intervention of the study and browsing at the subcutaneous injection of the study drug. Importantly, there was no treatment emergency use be it. Overall, safety of selapagrel was good And the drug was well tolerated. Next slide, please. Slide 39. So we see from this Phase 2 data, from the Phase 2 clinical development so far that we can tick 3 boxes: safe product, Fast acting and short duration. Seltagrel induces trophon plazhet inhibition. It is fast acting within 15 minutes of administration with The duration, siltogrel was well tolerated at both doses with no major bleed. With these data, we selected 16 milligram At the dose for further investigation. As mentioned before, it's important also to have The convenient mode of administration. Next slide please, Slide 40. Hydorshach choose to work with a leader in the field of auto injector To select a customized and customize the right delivery system, Ampharas has a proven track record in developing drug device combination products that are to the therapeutic needs and patient friendly. Together, we have developed a drug device product combination, Combining Adorcestershire's Sudhakar's product with the Antaresi subcutaneous QuickShot auto injector. Next slide, Slide 41. The Entrez auto injector was chosen for several reasons. Sure. It's robustness. As it will be carried by patients in their bag or their pocket wherever they go, 24 hours a day, 7 days a week, 3 to 65 days a year. The product has to be available all time. Given the emergency use indication for the Selatograde drug device product, technical reliability for successful injection is a key criterion. Ease of use and emergency readiness are essential for patient and caregiver to handle the device confidently during very stressful condition. During the development of the device, EYDSIA has conducted several human factor studies, including a validation study And caregivers of relevant age range in both sexes and in subjects with or without expense of self injection. Next slide, Slide 42. The final validation study in the relevant population was conducted in situation, mirroring the real life The results of this study demonstrated that the auto injector, the on device label And the instructions for users allow the users to perform their task. Next slide please, Slide 33. With these results, we can tick another box here from the prerequisites 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 patients that will 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 a study auto injector. The training material was developed with the education experts, cardiologists, nurses, feedback from patients post LMI On symptom recognition, addressing when the patients have to inject and how to do it, How to use our study auto injector and to call allergic services right after the injection. In the study, patients will also have Successfully practice a placebo injection prior to being randomized. Slide 45. With that said, we can now tick all the 5 boxes of all the prerequisites and we are ready to discuss the Phase 3 registration study. Next slide please, Slide 46. With the Selina in the SOS IMI, we will now put Selatovir 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 B2Y12 antagonist selato develop on symptoms prior to formal diagnosis and medical contact leads to improved outcome. To do so, the SOS IMI has been designed in collaboration with leading experts and has been discussed with health authorities. It is an international multicenter double blind randomized placebo controlled trial. In SOS IMI, the patient is empowered to make decision at the very onset of suspected IMI symptoms. This empowerment requires engaging the patients in recognizing IMI symptoms And take immediate actions. Next slide, Slide 48. One of the key questions is who will be enrolled in the study? Subjects will be enrolled in the study within 4 weeks of a recent IMI, either at high risk of recurrent IMI. And patients are considered high risk if they have either had another mortality infection with the previous year or if they have All other factors such as diabetes, age over 65, active smokers and so on. Of course, prior to being randomized to study the patients will have We tried and demonstrated the kind placebo inject themselves. This leads us to the next slide, Slide 49, We should be fixed how the study will be operationalized. Here you see a schematic of the study. Patient that had a recent IMI And 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 1 flash on 2 is our telotrale on placebo. Let them go about their normal lives, 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 IMI, they will perform the required set of action, First, self injection of Telatrade and immediately after called 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 Nofelatubre for the treatment of a suspected AMI in a few 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 selacobrel When self administered upon occurrence of symptoms suggestive of an IMI in patients at risk of having recurrence. The success of this will be measured by the grading of IMI on the scale from no macular infection up to this. All events will be blinded blindly adjudicated by clinical event committees to ensure consistency across the many sites and countries around the world. Similarly, the primary safety endpoints of bleeding will be blindly adjudicated by the Clinical Event Committee. So now Slide 52 coming back to what happens to Hi Mai today. With selatogrel, we are addressing the delay between symptoms and treatment, the period during which patients are most vulnerable. With selatogrel, we empower patients to take decisions prior to formal diagnosis with the purpose of saving lives and improve long term outcome. Slide 53. How could AMI be managing the future? As we see here, the CF administration has the potential to change the life The patient by slowing or stopping of the heart attack, early intervention leads to better outcomes short term and long term. The key words to remember are self administration of selatogrel using the auto injector as early as possible at the onset of AMI symptoms by EMPOWAL Empowered patients. It could change the path, the treatment paradigm of FMI. So FMI is the next study On the Selator Direct development, we look forward to reporting the outcome of Sohsi IMR in approximately 2.5 to 3 years from now. And with that said, I will hand over to Andrew to open the Q and 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 and A session, please? Yes, of course. Ladies and gentlemen, we will now begin our question and answer session. Once your name has been announced, you can ask a question. And the first question is from Peter Verdult, Citi. Your line is now open. Please go ahead. Yes, thanks. It's Peter Dole here from Citi. Thanks for doing the call. A few questions from me, please. Firstly, just the anticipated cost On the Phase 3 program, anything you could say about the powering of the study? And then looking ahead, if it 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 CSRL in acute MI. So I just wanted to get a sense of how much buy in you've got from the key KOLs in the U. S. And Europe? Okay, Peter. Thanks for that. That's a boatload of questions. Okay. So we've got 1 on anticipated costs, 2, on what are the pairing 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 partner and then fourthly, what are the KOLs thinking about this and what has their interactions with them. I will address quickly the cost one. I will refer the powering assumption 1 to Guy and then have the partnering and And KOL by Jean Paul. So the anticipated costs, 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 trial costs will exceed those that we had For Daridorexant, as we develop that Phase 3 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 $200,000,000 to $220,000,000 in total over the whole Lifetime of the Phase 3 program. Geet, 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 these questions. 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 an experience within the observation period. The number 2 is Also based on the probability that the patients will recognize And the symptoms and the cycle intake. And both of those are relatively unknown. And therefore, we make a number of assumptions On these numbers, to end up with a number of patients that have to be randomized are 14,000. Now, if you maybe your assumption is about So the effect size or the size of the effect we want to observe better than to say the effect size. And we estimate that we may be able to reduce the occupancy rent. It's a bit complicated here because We have a multilevel endpoint. As I mentioned, we fixed level from No events to date. So therefore, it's not totally the same for all different levels. But overall, It's a 25% prediction in the event right on active Comcast Festival. 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 Celatogrel, 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 smoking 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. I think the 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 cardiology, we wanted to have our device because as you know, The number of patients who reached the COVID crisis hospitalized because of myocardial infection 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 a MyoKadri infection 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 you get To be treated is very different and this is why the FDA thinks that this is a very Useful tool and that is really shown to work. People in very far remote The location will have this auto injector at home And could treat themselves why they will be transported to sometimes 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 sensors interested into the study. And I have to say that both in Europe, in the U. S. And in the U. S, this concept It's getting more and more traction and gets a very big support from key opinion leaders. Thank you. The next question is from Greg Zavonovich, Goldman Sachs. Your line is now open. Please go ahead. Great. Good morning. Good afternoon. Thanks for taking my questions and thanks for the presentation. 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 can 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 Variability that may confound the trial. So if you could address that, that'd 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 macular infarction before, this package is being tested. This package is being translated into all the different languages in 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 trainers, which will be done through phone calls. There will be re induction 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 It's 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, 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 his 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 is only taking care taking into account the patient who has injected themselves. And that's very important. This is why this type of it's not a detail. This type of important element Was agreed with the FDA because, of course, we didn't want to have patients We do not inject themselves and we are included into the study. I think it's important to know. Thanks, JP. 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 it's The 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 in endpoints going from No event to death. So the patient that will inject when actually they have no multiline infection and maybe Yes. Confusing the symptoms with something else will be counted as having none of the no, in fact, no deaths. So they will be in that category number 6. And this is accounted for in our sample size 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 statistical model. Okay. Thank you for that, Guy. And then My last question and then maybe I'll jump back in the queue is with regards to your FDA 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 Yes, that's important for us to keep in mind. Thank you. Yes, that's in general the interpretation of SPA. The SPA agreement means that if we conduct the study and we conduct it well, This is an important component as well. And the study delivered the results that I expected. The likelihood of approval is very, very high. It's never a 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. Okay. Thank you. And the next question is from Rajan Sharma with Deutsche Bank. Your line is now open. 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? Thank you. 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 a third of the patients will recognize the symptoms and self inject. This is just What 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. Thank you. And then maybe if I could just follow-up with a quick one. Just in terms of going back Commercialization, what do you think going back to your comments of it being a specialized niche indication, What do you think is the right size for a commercial organization and the infrastructure would you need? Okay. Jean Paul, do you want How large do you think the heart attack survivor patients 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 preliminary hypertension, we did a study in patients with a certain amount of limitation in work distance, But it has never been in our label something which was required to treat a patient 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 with prostate is 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 infection And you treat the patient with our auto injector, he will save him maybe in a A very large amount of time, we don't we say at least 30%, it will save the form of myocardial infarction. If it were the first multidrug infection, 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 myocardial infection and who never had a myocardial infection, also would not be able to recognize as well the myocardial Got you. But it doesn't mean at all that the FDA is going to limit our indication exactly To the high criteria of inclusion in our study. That's the number one. Therefore, the market is really clearly not only the patient who got the myocardial infection 1 year before Because if they got it 2 years, the risk of new microderall infection is lower, but it is still there. If they got 3 years before myocardial infection and they have diabetes, they still have a high risk of myocardial infection. 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 months before a 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 do believe that only cardiologist would prescribe such a drug. And I think it's quite a limited market. It's a limited size of Medical representative. 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 adherence, like for the EpiPen, It was a huge success because it's an insurance. It's a safety for the patient to carry some things because today, Imagine to get to myocardial infarction on the golf course or in the middle of nowhere, It's quite terrible because you have to wait for very often for a long time. So I think that Schedule it is to be prescribed it and it will be the least cost of marketing. Thank you, Joepel, for those clear statements. Operator, do we have any other questions? Yes, we do have a final question from Barbara Blaha, Credit Suisse. Your line is now open. Please go ahead. Thank you for taking my questions. First one, maybe I missed it, but how long do you think will this study take, Please observe, please. 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 our presentation, We should see the results in approximately 2.5 years. The time to set up the study, hopefully the subject To train them and to observe them will take a lot longer. Okay. Thanks. 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 the question. So I don't really Now why you have this 6 point scale of your efficacy assessment? Yes. So basically, the worst case is that the patients will die. The best case is that there would be nothing. And in between, we have several levels, non semi and semi, and we have also Different levels of severity with really 2 categories. So in total, it is 6 levels. It's important because we cannot have the survival study. Death is relatively infrequent and therefore, we also Want to look at the STEMI and non STEMI. And we also have an interest in the long term outcome of the patients. And the long term outcome, of course, is also driven by those who survive the acute event and maybe develop heart failure Due to the repetition of Mattel and Karsten. 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 hazard ratio, it's not exactly an hazard ratio, but it's similar to the hazard ratio. So they're all contingent And we have an anticipation that all of them all of the categories will have a reduction on Celatogrel, Except the category where there is no event, there will be an increase on CELA Togrel compared to placebo and for all the other reasons that we see. They all contribute to the study outcome based on the results and assumptions 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 Hep symptoms and then injected selatrobel and selatrobel helped to decrease This event will be described? Yes. And this is possible. It would be quite remarkable If this becomes the main issue and also that if they had an incident event, there is no biological Twice of that, for example, increasing property level. But clearly, there is a possibility that if the event is aborted very Which leads may be confused by those that injector for the wrong reasons. The blinded adjudication by The independent committee will certainly help us in that respect. Okay. Thank you. 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 do not. But I think that your question, it's an important question because It was really also the suggestion of the FDA about this continuity within the end I think they were really much in favor. This was discussed in the SPA. This is a very important element. Because what can happen Is that a patient who would have died without my auto injector now can survive. So the number of deaths can increase. But if you would have had a mild infection, then it can have a much milder infection. So if you would have, I would say, an infection with clinical symptoms, now it can have an infection with only Enzyme issues without clinical signs. And every of these steps is an improvement for the patients. And we wanted to capture all possible improvement for the patients, which are, I think, relevant. And this is why we made these 6 steps, which I think is a very elegant way to capture all the potential benefit. 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 we would, for example, In addition to this enzyme clinical sign and other elements to characterize the extent Of the myocardial event. And this was asked to by the FDA and this was, I think, and we I completely agree. This is the best way in my mind to assess the effect of this auto injector. Okay. Thank you. Thanks, Ivora. Thanks, Guy and helpful for those remarks. Operator, are there any questions left? We do have a question from Marc Antonella, Jefferies. Your line is now open. Please go ahead. Hi. Thanks for taking my question. Just a quick one. Not sure if you're not, I might have missed it. But if the patient in the study does have an AMI event and regardless whether it's A mischaracterization or not, do they receive and if they use the 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 your first event or not, it doesn't matter if they use the pen, the insect, They will get a receipt they will get a new pen and they can again be followed And potentially, in just another time. Absolutely. Okay. Thank you. 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 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.