Study Result

Jul 7, 2021

Press Release

Hello, and welcome to the Sunamp Pharma Audiocaster Teleconference. Throughout the call, all participants will be in listen Today, I'm pleased to present CEO, Jert Kornflesson. Please begin your meeting. Thank you very much. Thank you very much for listening in on this call, and very nice to see that so many of you have joined today. We look very much forward to discuss additional and existing results from our COVID study. And I'm delighted to be joined by our Chairman, Doctor. Torbjorn Bjarte our CFO and Founder, Doctor. Thomas Jonathan and very especially by Professor Mauro De Serra joining us from Brazil. Mauro has been instrumental as primary investigator in getting the study up and running in a very short time frame, and we have been very impressed with our collaboration. Move to Slide number 2. We will take you through a short slide presentation on our team finding And I will hand over the word to you Thomas. Please move on from Slide number 3. Thank you. So Slide number 3, please. I will go through a A short introduction to the principle behind the AP1189 compound and the way it address inflammatory disease and put that in perspective with regard to viral infection and more specifically COVID-nineteen infection. The compound is a small molecule, a biased agonist to mineralocarcin receptors and it works in a tube fashioned mode. It reduces inflammatory responses and at the same time, it promotes resolution, meaning that it stimulates antigen pathways that this and thereby facilitate clearance on inflammatory responses. The compared effect of this is that hyper inflammation, which is one of the devastating effects of COVID-nineteen infection, is modulated in a fashionable way. Next slide, please. The target for our compound is melanocortin receptors who are present on white cells, meeting in immune competent cells. We are focusing on and our compounds stimulate the MT1 and MT3 receptors, which is both present On white cells, including microphages. And to the right, you can see here a model of how the compound's dual action is mediated. In this case, we have a macrophage here. It's stimulated with a pro inflammatory stimulus that could be a virus infection. And in this case, by stimulating melanocortin type 1 and neoantacartin type 3 receptors, We reduced the pro inflammatory activities of the macrophages, meaning that the release of pro inflammatory cytokines, including IL-one, IL-six time is reduced but never blocked, meaning that we hardly induce we never induce immunosuppression, but modulate the inflammatory response pro inflammatory pathways in a beneficial way. At the same time, we have a larger fraction of the microphaties who go for classical pro inflammatory phenotype to a proven solving phenotype, meaning that it through what is called epheroscytosis and phagocytosis, type 2, clear up the ongoing inflammation. And again, this is a process that is significantly stimulated by our minimal cause in the seps agonist compound. Next slide, please. Microphases play a pivotal role in development of hyper inflammation and respiratory distress in COVID-nineteen skin infections. They are stimulated, as you can see, as highlighted here, and we'll not go into details to the left, through viral infections and And microphases is then generated from circulating white cells that goes into the lungs and then plays a role very, very high up inflammatory cascade. And the concept for our compound is, among other, to block or not block, but inhibit and modulate macrophage activity. So if you have the ability to reduce the macrophages pro inflammatory activity. You will reduce the influx of neutrophils and other pro inflammatory part of white cells and also reduce the release of pro inflammatory cytokines, not only with T cells. Call. So all in all, that's the microphases essential for our understanding of how our compound works. Next slide please. Our compound is a biased agonist. It means that it stimulates the receptor, the cyclic AMP, not through cyclic AMP, which is classical way to stimulate Melanoma Corcin receptors, but more but as you can see here to the cartoon, to the graphs up to the right there, it works through ERK phosphorylation and thereby specific stimulation on this pathway. And it does through binding to to an allosteric binding type on the receptor and thereby have a unique pharmacological effect on the receptors listen, thereby also on the inflammatory responses. So these responses, as I showed on the other slide, is associated with will choose pro inflammatory activity and at the same time, promotion resolution. We have By this, we decided to set up a collaboration and please go to slide number 7, next slide, where we have made a collaboration called Resovia Resolution in Viral Infection together with Maruk Taksaria, suite who is present on this call today and with Mauro Peretti at the William R. Research Institute in London, who is also a pioneer in resolution therapy, with the aim to explore the possibilities to with our pro soluble compound 1189 to see whether it will be possible to modulate viral infection where the first aim is to go for COVID-nineteen. We therefore set up investigator driven study in this reservoir collaboration with Mauro, a principal investigator. And the setting is study. We started up with an open label study where we tested safety of the compound giving once daily for up to 2 weeks in COVID-nineteen patients and then following this initial part, We continue in the 2nd part of study, which was a double blind placebo controlled study in a 2 to 1 randomization, meaning that we give Phase 2 who gives ATSI, we have 1 on placebo treatment and the compound is then given to patients as an add on to standard therapy. The inclusion criteria is that the patients who have positive COVID-nineteen infection, they had to be adult, meaning that in lifespan or age between 1885, a disease history for less than 15 days, and they would have a need for support with respiratory assist, meaning that they were having a need for supplementary oxygen on mask on the nasal catheter. And then of course, they should have signed an informed consent. The primary efficacy endpoint was time to respiratory recovery time at the time from initiation of treatment to the time where patients' saturation was defined to be higher the 93 or higher on ambient air, meaning that they would have normal saturation in the absence midst of supplements and in the absence of extra oxygen. Secondary readouts including data of hospitalization, certain 3 days need from mechanical ventilation and circulatory inflammatory markers, which is still a work in progress and we would look very, very much forward to quite an extensive exploratory work that we have initiated on this part. The study, as I said, was conducted in Belo Horizonte with Professor Mauro Teixeira as Principal investigator. And with this, I would like to give the word to Mauro. Thank you very much, Thomas. To the speakers. I'll just add to the slide that at the time this study was conducted, we virtually only had the T1 variant of the virus, Which is the gamma strain, the Brazilian strain. So in other words, we were actually dealing with a more severe variance of the virus at the time this study was conducted. Next slide please. Just to show that the baseline characteristic of patients It was very similar. They were on average 51, 63 years of age. That was mostly due because every time again vaccine was introduced to older people. So we were left with middle aged individuals, well balanced in terms of gender and well balanced in terms of comorbidities. And indeed, most patients who were hospitalized and are giving medication of placebo had a degree of comorbidity, which actually explains the age they were actually in hospital. The severity is moderate to not so severe, No, a new school score of around 5. They all needed oxygen supply around 4 to 5 meters and had an oxygenation index of around 200. So the baseline characteristic patients was very similar between them, Which allows further comparison. Next slide. And I like to think this is really sort of the clean of the result. The mean time to recover was around 10 days in placebo, 9.9, and it went down to 5.9 the patient. So this is a decrease of 4 days in the range of oxygen to reach a saturation of over 93% And I think if you look here to the right, a significant amount of patients actually gut data significantly faster. So there were a significant amount of patients that were actually Not needing oxygen supply by day 4. So that actually Leading as oxygen translated well in terms of hospital stay. Indeed, there was significant drop of 3 days in hospital scale. And again, if you look here to the right, Because we make fewer patients with oxygen until, say, 3, 4, It means that patients that were released from hospital at day 4 were mostly patients who were treated with the compound. Very strong balance here. If you look here to your right, about a third of treated patients were discharged from hospital Until day 4, because there was actually 50% of them already actually reached, with the total recovery. So this is actually really exciting because you had believed 4 days less of oxygen and 3 days less of hospital stay. And obviously, that actually reflects in the more severe phases of the disease. So fewer patients needed oral intubation or mechanical ventilation. So 17% of placebo treated patients went on to have an oral tube and even mechanical ventilation and about a third of that is precipitation. And If one looks at acute kidney injury as affected by increasing selumacreatin, about a third of patients of control. Patients had a degree of kidney injury and that was decreased almost by half in treated patients. Okay. As far as the safety, there were no I think we have to ask Going through the slides. Yes, I forgot. 2 15. So we are actually on Slide 13 now. I apologize for this. On Slide 12, I actually So the effects on the most severe patients, which is mechanical ventilation and acute kidney injury. And on Slide 13, the next slide, We are actually looking at the adverse event. Very much So we had no major adverse events that was associated with the medication. Usual adverse events were nausea and vomiting. At present, the medication is given as an oral solution. I mean, can you imagine Giving an oral solution to someone who has shortness of breath is not simple, It's difficult to breathe and taking something by the oral route as a solution. And so nausea and vomiting were the really most important adverse events. And if they were more associated with the AP-eleven eighty nine optical control. Otherwise, adverse events were comparable between groups and there were no severe adverse events And they're associated with the compound. With that, I pass it on to you, Thomas. Well, thank you. The side effect profile that we see here is very comparable to what we have seen in Phase 1 in the healthy volunteers as well as on our ongoing rheumatoid arthritis study. And nausea and vomiting is the most prominent. We have also seen temporary increases in transaminases in the study. In previously, but we also have identified that in placebo treated patients. And especially, we have reported from the Royal Metrology Pfizer study that the increases was present in placebo and not in the 100 milligram dose level. But so all in all, this side effect profile was what we expected and we believe at least some of it is to be, as Mauro mentioned, is attributed to the formulation that we are currently working with, which is suspension and that's why we are not at least call. We look very much forward to continue our development in the autumn with our newly developed tablet. As we did not go through as There was not shift through the different slides. I think it might be worthwhile just to jump back to Slide number 11 Or 10 actually, because when Mauro, he went through the data and he mentioned and showed very, very nicely that we have reduced increased or reduced time to respiratory recovery that reads clinical significance. Call. He also very, very highlighted very importantly that average time for hospitalization was reduced with 3.3 days. And as you can see here on Slide 10, this There is discharge from hospital is present in a significant amount of the 1189 treated patients already from day 1 off and whereas the first discharge on placebo treated was on treatment day 5. So and the next slide here on Slide number 11 showed room. What's Mario also highlighted that the oxygen needed for respiratory recovery at treatment day 4 was markedly lower on the 1189 treated patients compared to placebo treated and then hospital discharge, 1 third of the patient has left hospital before the first placebo treated. So with that in mind, I will go to Slide 14 for the study conclusions. And the conclusion is that we gave the compound as add on therapy to standard therapy that includes zotose dexamethasone. The typical dose is 6 milligrams per day. And in hospitalized patients with a need for supplementary oxygen treatment. Under these circumstances, the compound significantly reduced time to respiratory recovery by 4 days compared to placebo. It reduced the time to discharge from hospital by 3 0.3 days compared to placebo as an average in the full data material. It facilitated early discharge from hospital with 33% of all AP11989 treated patients discharged following 4 days of treatment compared to none of the placebo treated patients. It was associated with a reduced fraction of patients who develop need for mechanical ventilation. The numbers are small, but the take home message was now. That we more than halved the need for mechanical ventilation in the active compared to placebo. And also from a purely exploratory point of view, we look into to changes in creatinine. And by there, you are able to make a rough estimate on development of acute kidney injury. And again, the picture was clear that a smaller fraction of the patients on active had increased or had infection of the kidneys. Importantly, there were no treatment limiting adverse events attributable to the compound. So all in all, that is where we are right now with this compound with this study, which we find very interesting and look very much forward to proceed with additional activities within our Resovir collaboration. So let's go to the next slide, please, which is Slide number 15. The disease development in COVID-nineteen is associated first with a viral response phase and then gradually with an inflammatory phase in the patients who gradually developed with this hyper inflammatory response. Typically then, the initial presentation is shortening of breath. And then eventually, you could have developed more severe lung affection, what's called acute respiratory distress, but also affecting other organs, including the kidneys, circulatory and brain. And the aim is, of course, to get rid of the infection And if we have it, then to control this inflammatory phase of the infection. Today, NIH have a recommendation is to use monoclonal antibodies. If possible, give them prehospital. They are expensive and limited to use to more to where you actually have the money and availability of these monoclonal antibodies. Dexamethasone following a very compelling study from last year showed that low dose make sure that dexamethasone treatment giving a time of hospitalization could have beneficial effects. It has to be low dose as and thereby you reduce the unwanted side effects. But it is known that dexamethasone also in COVID-nineteen patients associated with infections and more than anything else, the black fungus disease as described in from India is to highlight as an example of a very, very, very severe dexamethasone induced side effects. Remdesivir was but besides that dexamethasone actually low dose control fashion works. And that's not at least that we on top of dexametasone actually can show a 4 days reduction in time to recover. You will find that very, very interesting. Remdesivir is also recommended by NIH and again has to be given in hospitals. So where do we see ACT-eleven eighty nine? The potential use could be as going in earlier than we did in the actual study. We'll go in as soon as the first symptoms of breath of shortness of breath was initiated And from there on, in other words, when the inflammatory patient inflammation phase is initiated. The ResOVIA 1 study this was designed in a way where we went in and gave the compounds in patients and actually patients who already were on dexamethasone. So the potential is, of course, to stay in this patient population, but there would also be a potential to go earlier on and dose prior to in the disease development and eventually look at the potential to reduce hospitalization. So with this in mind and these data, we feel an obligation that we and also a very, very high demand and within our company to continue the work within viral infection. And we would one of the first thing is to discuss with relevant authorities, including the authorities in Brazil To how to potentially could come to an emergency use of this compounds, but immediately and also in parallel with that, set up next study, a confirmative study of this compound's ability to speed up recovery in these patients. So speed up respiratory recovery, potentially reduce hospitalization. And then the aim is to conduct that with our newly developed tablet, who is going to be available at the time where we could have this study initiated and the study would from natural reason be in a continued collaboration within the reprophasortechs area. So with this, I would give the work 2 hour Chairman, Torbjorn Bjorge. Next slide, please. Thank you very much, Thomas. So on Slide 17 we are now. So first of all, I would like to take the opportunity to thank Professor Mauro the facility. And also thank very much the patients participating in this study. Room. Remember that the study was done in a very, very busy period in the hospitals of Brazil and this busy period continues to be. So we are very grateful for that. But I would also like to take the opportunity to express our gratitude to Cenac Pharma shareholders. We really, really like all the feedback, constructive feedback we get from you. Call. So thank you very much, and please continue to give us that feedback. So the drive for us at Select Pharma, but also all other biotech companies is really to develop the new innovator medicine that can transform the patient's life, that can transform how we treat the patients. It gives value to society, but it also gives value to the company's shareholders. We believe That the data coming from this study gives value to the patients. We believe that we can Transform the potential transformation of how to treat severe inflammatory disorders like Yes, COVID-nineteen inflammation. Please remember that COVID-nineteen inflammation is one of the worst inflammation you can think of. But it seems based upon these results, it seems that 1189 is a kind of tailor made for that inflammation. Discussion. So that's why we both see a big medical need. As you know, with current geographic hotspots like Brazil and India. I think the last week, it has been about 50,000 new cases every day in these countries. We also see some vaccine hesitancy, a new emerging virus variants, the delta virus space. The delta variant coming up and also the possibility of seasonal recurrences. We believe that treatment. Effective new treatments are still needed. And there are not many treatments, as Thomas said, that can really go in and change The pathophysiology, the cause of the COVID-nineteen inflammation. So we believe there's a big medical need out there. To come up with new and safe and effective oral therapies. So we have a clear plan forward. As Thomas said, We'll discuss the next step with regulatory authorities. Of course, they need to give us feedback on what they see in potential opportunity to get emergency use authorization. We are indeed keen to bring this therapy forward to the patients as soon as possible. And In that work, we also need to scale up the so called active pharmaceutical ingredients, the API And tablets manufacturing. Thomas Vosin, our Chief Operating Officer, do have the responsibility for that. Call. And as you have heard today, this is definitely going in the right direction. I also want to point out that The results here also gives a good, let's say, a good feeling or a good path forward to the opportunity to treat other very severe virus inflammation. And I'm thinking about the influenza, Thinking about dengue, that is again a big, big problem worldwide, especially in Brazil. This gives us the opportunity actually to look into this in more details in the Vesuvier collaboration, Where we have what we believe are the best investigators in the world within this space. So we are looking forward to the next steps. We'll work as compliant and as strict as we always do in order to secure these. But there are, of course, uncertainties in it. But we look forward to have the discussions with the authorities. And the new Chief Medical Officer, Anders Stu, will have the responsibility together with this to initiate these discussions, of course, also together with the Protesa Mili or Taxila in Brazil. And from that, Impella will set up a study that can give even more light on the opportunity for 1189 to fight COVID-nineteen infections. On the right side here, we have put up the expected milestones. And as a shareholder Of Sunak Pharm, you have been witness to quite some progress during the last 1 to 2 years. Of course, the first one was the interim data in rheumatoid arthritis. And this is still our main focus. It is to bring 1189 to approval concept and further on, hopefully, in rheumatoid arthritis that do have a big, big medical need as well. We among the other milestones, I can mention the new potential intellectual property for AP1189. We are building several layers of protection, Which is important, of course, in terms of the market exclusivity for 1189 in different diseases. Room. And we are working on the tablet and will soon with more news on the tablet formulations. We also are, of course, looking forward to have the full top line data in the rheumatoid arthritis study in the end of our Q3 this year and then decide on how to proceed with further development of the pipeline. But all in all, I think it's a fantastic good opportunity. We have a good start here with 1189 showing even effect in the worst case inflammatory disease. And we have a few coming through. The first is from Adam Carlson of ABG Sundal Collier. Please go ahead. Your line is open. Hi. Thank you for taking my questions. A few from me, if that's okay. First one, just wanted To confirm that the data presented last week was based only on the randomized blinded portion of the trial, I. E. The 36 AP11A9 treated patients versus the control arm and that this was the primary statistical efficacy analysis outlined in the statistical analysis plan Or whether this additional with the 6 patients from the safety run-in was part of the statistical analysis plan originally? Thank you very much, Adam. Thomas, can you take that one? The data we presented last week was yes from the randomized part 2 of the study. The data we present here is on the full data set, which To be considered would be logic to do and also a part of the original plan As the comorbidity and in the patients and the way it was treated was comparable to what has been done in part 2 except for the fact that the first 6 patients was open label. In any case, you have to have in mind that this is the first exploratory data And that we have to and that we are planning and we will continue developing in this program. Great. Thank you. And on further potential efficacy measures. Were there other secondary or exploratory endpoints That you recorded, thinking specifically about sort of survival, if there's anything to be said about that. Obviously, a small sample size, but it's still interesting to hear. And on the endpoints not yet reported or so, how if If there's anything you can see on how they stack up relative to the data we've seen so far in terms of trends towards benefits, if there's anything that looks more neutral or so? Conference. First of all, within the study period, we did not have any basic cases. And that means up to we follow them up to day 28. With regard to additional readouts, there will be. We have importantly and more than anything else, we have all the samples for exploratory and secondary relapse, including for cytokines order, inflammatory pathways, also a lot of exploratory pathways to get more understanding and mode of action and the potential of Our compound, the sterilized resolution therapy in COVID-nineteen infection. Great. Thank you. Listen. And on the safety tolerability side of things, just curious on the frequency, but also the severity The nausea, whether that was comparable between the two arms and beyond that, whether there were any treatment related discontinuations or dose reductions in the study? We did not have. Yes, sorry. Yes. What we can say is that we had all the patients was treated with the compound. In some patients, both on active and placebo, stopped treatment when they left hospital. Room. And we and I think that Mauro, Doctor. Sassez, he highlighted that we are working currently, we are working with the suspension, which for the more severe cases was an issue, meaning that if you are very, very short in breadth to drink our suspension was challenging, but we managed to get through with it. And that's an important part also for the future that we will continue to develop the teleconference. With regards to intensity of the side effects, it has been reported As Anne also highlighted that the frequency of adverse events were higher in active than in placebo And most likely has to do with the again with the compound. But in most cases, for not to say at all, it was moderate low intensity. And what we typically have seen with nausea is that it's something that comes relatively fast After intake of the compound, in most cases, actually before we reach Tmax in blood, meaning that we believe that it may very much meeting with the coronary formulation. That has been applied. Okay, great. And a question On any other potential treatment, Should we say investigational use of anti IL-six or JAK inhibitors as well for COVID-nineteen presumably this none of the study participants received any other treatment And standard of care dexamethasone and placebo or EB-eleven-nine or were there any investigational other treatment? No, what I can say is that let me then take it. Dexamethasone is the setting in Brazil is That patients in this study here typically were referred from a polio clinic, you could say a secondary ward. When they came with initial symptoms, shortening of breath, then the Patients are set on low dose dexamethasone and in some cases also on antibiotics. And then if they develop further the need for supplementary oxygen, they will refer to hospital at which time point. We then Gave them the opportunity to offer them the opportunity to participate in the study. So As I understand, there is not giving ridemsimur, there is not giving IL-six antibodies antagonist or any of the monoclonal antibodies. Okay, great. Can I Yes? Just to add to So Redensivir is not approved for use in Brazil. And actually, the effects of Redensivir at this group, which is already hospitalized, It's very low. The one thousand six hundred is again not widely available at all And it's separated for patients who are a little bit more severe. But all of our patients, They had an indication for dexamethasone. They were given prophylactic heparin and they were given antibiotics until we were sure they did not have any bacterial infection at the time antibiotics were removed. So we need standard of care For Brazilian Health Ministry. Okay. I'm sorry, steroids we're giving for 5 days. That's also again standard of care. Great. Thank you. And I don't know if it was shown In the slide on the baseline characteristics for the 2 groups, but Was there any difference in the Difference between the two treatment arms in terms of the course of the disease, say, days post for symptoms that they were randomized and initiated in the trial? Or is that equivalent between the two ones? It was not some, but that's equivalent as well. It's around 8 to 10 days after onset disease. So we are reading to the inflammatory phase. Great. Thank you. And maybe just one last question from my side. Just curious on the obviously discussions ongoing now about next studies and design and funding support and so on. But is there anything that you can say about the kind of the degree of funding support you would need to move forward with the confirmatory trial? Or I guess put another way, how much of your current cash reserves would you be willing and able to put towards another COVID study? Yes. Thank you for that, Adam. We first need So talk to the authorities and think about the next step in terms of how big should such a trial e dar, how big should it be. However, remember, this was a trial in a total of around 60 patients, right? And we showed the results we did. And with the power calculations involved in that, I think we can do it smart. And Thomas is already together with Mauro thinking about this next trial. So we don't foresee a very big trial. In terms of the funding, we do have cash in the bank through the last financing. We will talk to authorities as well about funding, But we are a public company. So what we believe is important here is that we get the next trial out to the patients to see if we can move this forward. Meeting. So as soon as we have the next trial set up, we will report report back to the market about how big it should be and the potential progress with the authorities. Okay, great. That's helpful. Just one final follow on on that question, perhaps for Mauro. Just Curious to understand the dynamics in Brazil a bit more in terms of the EUAs. If you look at COVID treatments granted EUA in the U. S. By the FDA, trials of a few 100 to a few 1,000 patients have been needed. Is there anything that you can say in terms of the evidential burden that Would be typically required for an EUA in Brazil? Would it be comparable to what the FDA are looking at? Or is it reasonable to Suspect that they would be happy with the far smaller trial? Call. I think as long as we found a trial for another program member for showing efficacy, Brazilian authorities, which is and these are real totally aligned with the FDA and EMA in terms of the acceptance strategy. So we will just have to make sure that we design the trial With the appropriate end numbers. I think for most studies with drugs, we are talking about below 100 To show you the efficacy, whereas vaccines will go for the 3,000. The rate of the gene in these patients is very high. So that tends to lower any number considerably. Did that answer your question? Yes. Yes. No, that's helpful. I gave that. Yes. Thank you. Listen. So Thomas, would you add something? Yes. We were just to say that one thing is to show efficacy. The other thing is to convince listen. That agree with the authorities that the safety database is sufficient. And there we have to have in mind that we in parallel with this program have And our main program, environmental autotripsy, where we also generate on a continuous basis, generate data to the overall Sensi database, which would eventually be part of the overall evaluation from New Horizon. Okay. Great. Thank you very much. Thank you, Adam. Okay. Could we have the next question, operator? That's from the line of Sebastian van der Solst, Tuuskampen. Please go ahead. Your line is open. Hi, guys. Thank you for taking my questions and Congratulations on the results. Thanks. First of all, I did not really quite catch the comment that Doctor. Mauro made regarding the Ghana versus Delta, sorry, could you please repeat that? Karru? So the Delta is only coming into Brazil at this stage. So we've had a few dozen cases at the moment. So that's why everyone is really worried that the epidemic may revise in the 2nd semester of the year. So what I meant is that for during our study, We had more than 80% T1 strain, which is the gamma strain that is circulating in our region at the moment. Virtually, there are no wild card strains anymore. And at this present moment, most cases are to Q1 and the worry that gamma has arrived and every The place that has arrived, so Delta has arrived and it has taken over for gamma in most places that it arrived. So That is the outcome for Brazil. And I suppose one of the advantages of inflammation host based therapy Is that actually you don't focus so much on the virus itself, but on the disease caused by the virus, which It seems to be similar and perhaps more severe in the new virus because the viral load is much higher. Okay. Got it. Thank you. And then regarding the rationale for designing the open label part of the trial, Why was that included? And were there maybe patients selected more specifically for that open label part of the study? Or Well, what's the rationale? Thomas? Yes. The rationale was very clear that it was first time this compound should be given to COVID-nineteen patients. So from a safety perspective and also to be in alignment with the local authorities, we made the decision to start off with an open label, 6 patients to get a grip on the safety profile and can report that back. And then in order to, you could say, show that safety first before anything else. The next thing is then if you go in and look at the profile of these 6 patients, they are with regard To co morbidities and severe severe disease at the time of inclusion is comparable to the rest of the population. So Sebastian, please remember that the selection criteria for these patients were exactly the same as for the randomized study. Yes, very clear. Thank you. And then I was thinking regarding the Congruiter, sorry, do you think that a similar design is possible? I saw what you showed in the slide, but Regarding the endpoints, what are you thinking of? And then also, you mentioned that you wanted to conduct the trial with the tablet simulation. Does that also mean that the trial will likely start after the bio exacelone study is completed? Thomas, let me start from the back. With regard to the tablet, from From a strictly regulatory point of view, we have all data from all in vitro experiments, all characterizations, including the dilution profile and so on. In addition to that, we have relevant exposure data from animals this that support that we can go directly into man. The reason to why we would like to spend time And money to make a PK Biorequivalent study in parallel with the activity we are going to set up here in COVID-nineteen is, of course to have this confirmed in humans and that also from historical reasons as I as we at an early stage In this company developed a tablet that turned out to have a very, very unpredictable PK profile, but that was simply completely lack of knowledge of where we are now. And now we have a tablet and we will go fast into patients. So we actually believe that we In parallel, we'll set up a study and also we will be free ready. And Whatever we are doing will biorecurement will not be as stable for the development Of the next gen cluster in COVID-nineteen. Okay. And then regarding the timing, would that then be Q3 or Q4? Realistically, it takes at least from now to get the interaction with our authority and set up the study, get 30 minutes and down there get all the approval. It will take 3 to 4 months. Okay, great. Thank you. And then So Sebastian, just a note here from me also on the, let's say, the results, for example, in the acute kidney injury. As we know, about 90% of patients with very severe COVID-nineteen ARDS infection. They develop acute kidney injury, which prolongs the disease tremendously. Zoom. So the signal we get here is also quite positive. And we know this back from The Action Pharma Days where we did development of another molecule in Another melocortin receptor agonist in acute kidney injury that we can actually Impact the degree of acute kidney injury. So that's an interesting, let's say, Interesting observation we see here as well. Just a note. Yes. No, that's interesting. Thank you. Then my last question. You mentioned that this The collaboration was set up to investigate the use of AP1189 in other also in other infectious diseases. Are there any specific indications that you are thinking of and that you would look forward to quickly enroll maybe next year? Thomas and Mauro, would you comment? I think yes, actually Mauro, I think That it would be fair to say that you have been a pioneer in understanding of resolution therapy in Enviro Infections with regard to not at least Biflanta and Denke. And perhaps you could comment. So I actually lost a little bit of the communication. So In a Tel Aviv, I think we will try. We are already working with local authorities this to plan the study and start this semester. In terms of outlook for all the viral infections, we have actually tested that experimental in the virus model. And before COVID, we have a line of research actually checking for resolution therapy in the context of Pifurinza. And results are as exciting, at least experimentally as for COVID-nineteen. And to be honest, that's what we were aiming for before the COVID-nineteen epidemic. And obviously, for our setting, There is always the there's a huge interest in dengue and diseases caused by albovirus infections, albovirus. So I think there is also a lot of interest there as well. I'm not sure whether that was your question specifically, but That's my feeling towards your whole area of research. Yes. Thank you, Nava. That's exactly what I was asking. Thank you. Listen. Yes, come on. No, I was just going to add experimentally as well, One of the problems of viral infections is that they are commonly followed by bacterial infections and that actually In the cause of death in many circumstances. So again, experimentally, what we've shown is that we've never seen this any form of immunosuppression caused by ProResolution Therapy. In other words, Because post inflammatory therapy decrease the viral damage, the bacterial infections that follow viral infections tend to be much less severe. And so and they are safe in the context of bacterial infection. So I think there is a lot of mileage whole field of research. Okay. So that's very exciting. Yes. Sebastian, we see a big medical need both in dengue, of course, but also in influenza. As we all know, we are hit survey by influenza every at least every second year, if not every year. And especially the elderly population die from severe inflammation in, for example, in the lung. So we see a big, big medical need here. Okay. Got it. Thank you very much. And I will jump back into queue. Okay. Operator, do we have any more questions on the Q and A? Yes. We have one further one in the queue. That's from the line hands of Peter, a Private Investor. Please go ahead. Your line is open. Thank you. And thank you very much for the nice presentation and very I have a question regarding the advanced event, and I would like to hear if you could Elaborate a little more about in of the increase in the transaminases. And Was it very severe? And do you see any direction between left inflammation and AP1189? So could you please elaborate a little more about this? Thank you. Thomas? Yes. We have We saw one was reported to have a more than 3 times increase in transaminases. It was patients who at the same time developed sepsis. And the question is and it is expected in such patients that the liver can be affected as well. We have but besides that, it was typically what we have seen was 1 to 2 times up compared to upper normal level. It was also seen in the placebo treated patients. And honestly, it's expected in this patient population. So in order to perhaps answer the question the other way around is that we have and we reported last year in November that we had In our rheumatoid arthritis patients where we give the same dose of the compound on top of methotrexate, we have seen no treatment related increases in transaminases. And again, what we have seen has in all cases been isolated increases that was coming back to normal within a few days. Okay. Thank you very much. Operator, do we have any more questions here? Currently, there are no further questions in the queue. Okay. We have received some questions. Maybe we should take 1 or 2 of those before we start. And one of them is a statementquestion. It says, ARDS is acquired in hospitalization mainly by bacterial infections. What are the plans to look at this in the Resevia collaboration? Is this in the pipeline? Or will you first go the wild route, dengue and flu? Thomas and Mauro? I think that it would be as Mauro just highlighted, bacterial infection is often coming secondary to the viral infection. So you could say that we and we have and one potential benefit of the resolution therapy with our compound would be to reduce the risk for bacterial infection. So I think that the right answer would be that we in the Respiria collaboration Is focusing on the viral infection as a first step and then exploring to the possibility and what is actually is going on with bacterial infections and the severity in the patients that we are going to examine in the future. Okay. Thank you. I have another one here. Thanks to the results in ARDS. Would you revise your current plans for other indications in the inflammatory diseases? And the answer is no. We will add to this task in COVID-nineteen as we have talked about today. However, the indication in rheumatoid arthritis is running as planned and the indication in Nephrotic syndrome, exactly the same. So we expect in Nephrotic syndrome, we expect results in the end of this year. And in Wilmotatrade, we expect top line results in the end of Q3. Let me take a last question here, and that goes, can we expect your priorities to be pragmatic When it comes to emergency use, considering the great need, or will they criticize the unusual method of combining open label data and double blind data when demonstrating statistical significance. Good question. I would say that they look at the quality of the data. And as we have talked about today, we do expect in the base case that we will do another study in order to confirm these results that we have talked about today. However, we cannot predict how the authorities will react. So We will need to have the discussions with them and then go from there. But that is our commitment that we will have those discussions in due course. So now the clock is a bit over 2 pm. I would like to on the behalf of the team, Cignac Pharma team and Mauro, I would like to thank you so much for participating in this call. We appreciate all the feedback that we get and talk to you soon. Again, thank you very much.