Hello and welcome to today's investor call with Sedana Medical. With CEO Johannes Doll and CMO Peter Sackey will talk about the SESAR study results. After the presentation, there will be a Q&A, so if you're calling in and want to ask a question, please press star nine to raise your hand and then star six to unmute yourself when handed the word. With that said, I hand over the word to you guys.
Thank you very much for that introduction, and thank you very much to everyone for joining us in this investor call today. We have had a dramatic reaction on the stock market yesterday following the publication of the SESAR results, an investigator-led trial that was performed in France. Our main goal with this call today is to address your questions. We will make sure we have sufficient time for that in the end of this call. Before that, we will share what we know about this study at this point. Even though it is not our study and not our drug used in the study, we will make an attempt to offer possible explanations for why we are seeing the study results.
We will talk about what this could mean for us as a business and what actions we are taking on the commercial side to both capture the opportunities that arise from this as well as mitigate possible risks. With me, I have our Chief Medical Officer, Peter Sackey, today, who will start us off now. He is actually joining us from the ESICM Congress in Brussels, where the results of the SESAR trial were presented yesterday and where he also had the opportunity to discuss the results at an evening event with 20 top sedation key opinion leaders that Sedana Medical has organized. Peter, please.
Thank you. We can take the next slide, please. Yes. Just a short interpretation and the view on our clinical development program as we move forward. Next slide, please. The SESAR study was inhaled sedation with sevoflurane in acute respiratory distress syndrome. This was a study that was in part supported by Sedana Medical. The primary source of funding was the French Ministry of Health. This was a so-called investigator-initiated study or investigator-initiated trial. These are driven by independent investigators, physicians that want to look at a clinical question. They determine the protocol and lead the study. We are minimally involved. In the case of SESAR, there was a question from the first author from the team in Clermont-Ferrand in France for supply with materials and also funding for training by training us.
At that time, when we had those discussions with the investigators, we were developing isoflurane for sedation. At that time, there was no approved inhaled sedative. Based on the pilot study that was performed by Matthieu Jabaudon and the study team that demonstrated benefits of sevoflurane for 48 hours, Sedana Medical decided to support the study. We can move over to the next slide. The whole idea of supporting that study was to interact with a key opinion leader who was very interested in inhaled sedation in general. He chose to use sevoflurane. As I mentioned, we did not have any approved drug at the time. There were also some things that were not known about sevoflurane for this indication at the time.
It looked like a promising opportunity, even though we were pursuing a different drug for good clinical medical reasons, I would say. Looking at the SESAR study, this was a study looking at patients with moderate to severe acute respiratory distress syndrome. The intervention was inhaled sevoflurane for a week, up to a week, initially for deep sedation and thereafter lighter, compared with propofol that was supposed to be used in the same way. The primary endpoint, the outcome, was days alive without invasive ventilation through day 28. Next slide, please. Seven hundred patients were randomized into these two groups. We're not going to detail about inclusion-exclusion criteria. We'll just move on to the next slide. This was a big study with sevoflurane. Here are some results. What we see here are the different sedation levels throughout the first week of treatment.
On the left, we see sevoflurane, and on the right, we see propofol. What I can tell you is that the dark blue portion of the bars indicates very deep sedation, the deepest you can actually achieve on the sedation scale called Richmond Agitation- Sedation Scale. If you look carefully, you will see that the maximal and the minimal RASS level was deeper for sevoflurane, both the maximum and the minimum, compared to propofol any given day. The total sedation duration in both groups was seven days, and the total duration of pharmacologically induced paralysis was five days. This is a little bit different from what they had intended. It was to be two days of deep sedation and paralysis, and thereafter lighter sedation. Move to the next slide, please.
Looking at the sedatives they received in the sevoflurane group, they received more propofol than the propofol group received sevo. We will come back to that. You can see the blue indicates sevoflurane on the left side, and then the striped lines, the striped part of the bar shows the proportion of patients that also received propofol. We can move to the next slide, please. The primary endpoint, as I mentioned, was ventilator-free days in the first 28 days. This implies that patients are alive and liberated from mechanical ventilation. Should you die anytime in those first 28 days, you are assigned the value zero, and the maximum value is 28. That is if you were to be extubated and stayed alive for 28 days. If you look at the next slide, we can see the results in this study.
The two very high bars are showing the zero ventilator-free days, and there were more of them in the sevoflurane group than in the propofol group. The median difference between the groups was 2.1 days. 2.1 days more ventilator-free days with propofol compared to sevoflurane, which was opposite, contrasting to the hypothesis that the investigators had. Next slide, please. This was largely driven by higher mortality in the sevoflurane group. You can see the cumulative incidence of death is higher, and it separates, the curves separate already in the first week of treatment. The mortality at 90 days was 52.9% for inhaled sevoflurane and 44.3% for propofol, which is, I would say, for a 90-day mortality, it's quite in line with other studies. The propofol mortality, the sevoflurane mortality is slightly higher. Next slide, please.
Looking at the secondary endpoints, I've highlighted the seven-day mortality just to show that there was already a difference in mortality during the treatment period in the first seven days. You can see 19.4% in the sevoflurane group versus 13.5% in the propofol group. Next slide, please. Why did these patients die? The main differences in causes of death, and this was free text that's been transformed into categories by the investigators, was multiple organ failure with slightly higher numbers. The randomized groups were similar. If we look at the numbers, they should be the same. If they're different, it means that the higher number indicates a higher mortality in that group. Multi-organ failure, refractory hypoxemia, and refractory shock. The biggest difference you can see was refractory shock: 15 in the propofol group and 30 in the sevoflurane group.
Let's move to the next slide, please. How could one interpret these results? We had this discussion together with the main investigator and other people knowledgeable in sedation, ventilation, and also in inhaled sedation yesterday evening. It was a very interesting discussion. I would say that the three drivers, I would say, among experienced researchers, clinical researchers, was really the impact of COVID-19, likely high doses of sevoflurane, and also sevoflurane-related renal failure. We're going to go a little bit into depth on those three aspects. Move to the next slide. COVID-19 came as a surprise in early 2020. The clinical trial, SESAR study, started in May 2020. That was about when it was at its worst. Most of the ICUs that were in SESAR were relatively new or completely new to inhaled sedation when they started.
This meant that there was an impact on the way we could help with training. There was also an impact, of course, locally on training. Communication teamwork was impacted severely during COVID. This had impact both on the conduct of the study and most likely also with the new therapy that inhaled sedation implied. On the right there, you see me during COVID. I worked some extra shifts in Karolinska University Hospital. It was very clear that it was difficult to do sort of new things, complex interventions, to get support for young people working or people temporarily working to understand anything sort of that was out of the ordinary.
One of the things that was done in the study due to COVID-19 was that the initially planned monitoring of sedation depth, either with the processed EEG, electroencephalogram, or with the end-tidal concentration of sevoflurane, that was initially mandatory. The investigators, this was Matthieu shared with us yesterday, that that was removed, that requirement to monitor and record the values because of COVID-19, because it became more cumbersome. As I said, this whole scenario with COVID-19 implied that the proficiency in managing any novel therapy was likely disfavored. Propofol is something that has been used for a very long time. Many of these patients were on paralysis also.
That means that not having any more objective than the sedation level clinically or sort of a tool to assess sedation would make it quite difficult to dose sevoflurane appropriately, given that it was a new drug. If we move to the next slide. Why do we say likely high doses of sevoflurane? When RASS could be done, it was deeper for sevoflurane than for propofol. An indicator of sedation level is, of course, the clinical response to stimulation. It can also be EEG monitoring. For inhaled anesthetics, you can also measure the concentration, which can help guide you, give you a feeling of whether you're on the right level or not. Yet another indicator of sedation level is whether or not the patient has low blood pressure or not.
Typically, an agitated or distressed patient has high blood pressure, and a very sedated patient has very low blood pressure. One of the drugs used to increase blood pressure in that scenario is norepinephrine. This drug was almost 50% higher in the severe group in the most days during sedation, the first week, indicating that these patients were likely over-sedated. Also, looking at the separation of mortality in the first week, that indicates that part of this excess mortality was likely directly related to the differences in the groups, meaning treatment-related. I showed you the causes of death where mortality differences were largest when it comes to circulation, so circulatory shock. If you are hypovolemic, which these patients might have been, you're extra sensitive to any sedative, I would say. This could be one reason for this excess mortality in circulatory shock.
It was not deemed to be severe infection, for example, which could be another driver, like severe sepsis that could be a driver of circulatory shock. We move to the next slide, please. Then we come to the sevoflurane-related renal effects. This is something that little was known about in 2018. There were a few publications indicating there might be some renal effects of sevoflurane. Since then, there have been an increasing number of publications about this renal dysfunction. It's typically related to the dose and the duration of sevoflurane administration. Giving more than 1%, which was likely the case in most patients in this study, and giving sevoflurane for more than three days is strongly associated with the development of what's called nephrogenic diabetes insipidus, which means you have polyuria, so high urine output, and hyponatremia.
In a recent cohort study that we have personal communication with the last author of the SESAR study, they found polyuria to occur in 40% of patients treated with sevoflurane for more than 24 hours. That in itself can cause hypovolemia and higher circulatory vulnerability to sedatives. As for hyponatremia, that is an indicator of subclinical diabetes or overt diabetes insipidus. Looking at the sodium levels in the patients in the sevoflurane group, they had an increase in sodium levels during the first week, whereas the propofol group did not have any change. Also, they did have a higher proportion of patients developing renal dysfunction according to criteria called the KDIGO criteria. This itself is a driver behind the multiple organ failure as well, because when you look at multiple organ failure in the ICU, you include renal function as one of those parameters.
That was also one of the increased mortality causes, which was multiple organ failure, which ultimately leads to withdrawal of care. If we move to the next slide, please. Regarding this renal dysfunction with sevoflurane that little was known about five to ten years ago, there's another study that was published last year from Beatrice Beck-Schimmer and her group in Switzerland. They found that 39% of patients receiving sevoflurane during COVID-19 had acute kidney injury, whereas only 6% of the intravenously treated patients had that. We can move to the next slide, please. I would say that this kidney injury related to sevoflurane administration has not been demonstrated for isoflurane. Sedana Medical has sold over one million ACDs since it was approved in Europe. The estimates are somewhere between two-thirds and 75% of these ACDs being used with isoflurane.
There are multiple case reports and case series with sevoflurane-induced renal dysfunction, but they're known for isoflurane. Professor Robert Sneyd from the U.K., who is completely independent from Sedana Medical, wrote in British Journal of Anesthesia in 2022 that it might be advisable to not use sevoflurane, but rather use isoflurane for ICU sedation, not only because it's approved, but also because there are no indications of any toxicity with isoflurane. We move to the next slide. What do we know about this? If you look at volatile anesthetics, typically, the metabolism and the toxicity are quite linked. Methoxyflurane was an old volatile anesthetic that was very popular in the 1960s. It turned out to cause polyuric renal failure, a bit similar to what sevoflurane seems to do when you give it for a long time.
It has very high metabolism, methoxyflurane, about 50%. Halothane has metabolism about 20% and has been associated with the development of halothane hepatitis. If you look at the differences between ISO and SEVO, sevoflurane has an approximately 5% metabolism, whereas isoflurane has approximately 0.2%. That is a 25-fold difference in metabolism of isoflurane. As I mentioned, we are not aware of any isoflurane-related renal dysfunction, even after long periods of isoflurane sedation. Generally, there are no reports to our knowledge of any long-term detrimental effects of isoflurane sedation. Next slide, please. When it comes to our own trials, we have the Sedaconda study, IsoCOMFORT study, and the two US INSPiRE- ICU one and two studies. I just wanted to give a brief view on them and share sort of the results that we have to date. If we move to the next slide, please.
We can move to the next slide also. The Sedaconda study was published in Lancet Respiratory Medicine in 2021. This was an open-label, randomized controlled trial that we had agreed upon the design with BfArM, the German competent authority. Patients were randomized to either isoflurane or to propofol for 48 hours. The study demonstrated non-inferiority versus propofol, reduced need for opioids, and also shorter time to wake up day two. This is all consistent with what was known about isoflurane in smaller trials. As I mentioned, this led to the approval of isoflurane for adults. Can move to the next slide. That intervention was only 48 hours. What we did was to post-hoc analyze the patients who, after 48 hours, remained on the study drug or patients that only received the study drug and were extubated within the 48 hours. We call this the non-switcher study.
Looking at the sort of real-world scenario where you receive only one drug, either isoflurane or propofol, until you no longer need sedation, demonstrated benefits in terms of more ICU-free days with isoflurane compared to propofol and a trend to more ventilator-free days with isoflurane compared to propofol. Benefits for patients and for healthcare. Next slide, please. Looking also into the need of additional sedatives, less additional sedatives were required in the isoflurane group. Also, which is reassuring, especially in light of the SESAR study results, was that fewer patients required renal replacement therapy in the isoflurane group. We saw no indications of any renal harm in neither the original study nor in the post-hoc analysis. Next slide, please. IsoCOMFORT was the follow-up study that we were required to perform based on our adult indication. This was performed in four countries.
We can move to the next slide for children between age three and 17. What we found in the study was that isoflurane was non-inferior compared to midazolam, the only approved ICU sedative for children. Next slide, please. We also found opioid requirements to be significantly lower during treatment with isoflurane compared to midazolam. Baseline was similar. In the isoflurane group, there was no need to escalate, whereas in the midazolam group, opioids were doubled during the treatment period, which is most likely related to the tolerance development that children exhibit when it comes to sedatives and opioids. Also, sometimes opioids are used as co-sedatives. Next slide, please. Finally, for the pediatric study, we found a shorter time to extubation and a more predictable time to extubation. These are Kaplan-Meier curves. You can see the probability of being extubated.
The blue line on the left figure shows how patients are extubated within a very short time. They are all extubated within a very short time when the aim is to extubate them. Whereas in the group of midazolam patients, there's a wider spread. Coming back to one of the main features of isoflurane sedation is that the wake-up is short and predictable, which allows for planning of extubation, which is a very vulnerable phase for patients, and also progressing care, enabling patients to get mobilized and leave the ICU. This was replicated in this study when compared to previous data and compared to the adult study. Next slide, please. We have the INSPiRE ICU studies that we completed last year and that we're working on analysis and preparing for our NDA submission in the US, also isoflurane. Let's look at that next slide.
Thank you, Johan. This is just the lead investigators and steering committee, which are key opinion leaders in sedation and ventilation in the U.S. They're well recognized. Most of these people have been doing these types of studies. They led the study together with Sedana across 30 sites in the U.S. We enrolled 55 and 55 patients in the two studies. They're two identical studies comparing isoflurane with propofol, once again for 48 hours. Next slide. Looking at the results, we've already presented the high-level results. What we could see was that in both studies, isoflurane was non-inferior to keep patients at a target RASS level, which was between minus one and minus four. Minus five was not included in the sedation target.
You can reach that, as you could see also with the SEVO study, but that is not typically the target you should aim for when you're sedating patients. The proportion or percentage of time at target was slightly higher in INSPiRE ICU two. It could be a learning curve, both in our education and also working on sites to really struggle to maintain target-level sedation. These were blinded assessments. The pictures you see below there show all the different analyses we ran. A number of sensitivity analysis and supplementary analysis. All of them show that these findings are robust, that this is non-inferior for sedation. Next slide, please. We also described on a high level that the safety in these studies indicated tolerability of isoflurane.
Looking at the serious adverse events in the respective groups, we found similar serious adverse events in % for isoflurane and propofol in the first study, slightly higher for propofol in the second study. Overall, serious adverse events were slightly less incident for isoflurane than with propofol, which also is very reassuring. Next slide, please. Now I think it's your turn then, Johannes, I think. Yeah?
Yes. Thank you, Peter. Now you've heard that SESAR was not our trial, that a drug was used that is not ours, that there are important differences between sevoflurane and isoflurane when it comes to things like toxicity and the metabolism, and that, of course, we remain very, very convinced of the benefits of our own therapy using Sedaconda isoflurane based on all the clinical evidence that Peter has just repeated.
Still, I know, of course, that there are concerns that these SESAR results might, in some fashion, have a negative spillover effect on our business. I will share some facts that are hopefully helpful in approaching that question and share with you our current best view on how to think about the commercial implications. We have two main objectives in dealing with these results. First and foremost, there is an opportunity in this, and we have to make sure that we capitalize on it. The authors of SESAR have come to the conclusion that sevoflurane should not be used for inhaled sedation for patients with moderate to severe ARDS. We full-heartedly agree with this. You should not use sevoflurane.
You should use the only product that is approved for ICU sedation that has very clearly positive clinical evidence and that is making a difference for many thousands of patients every year. That is obviously Sedaconda isoflurane, so our drug. The primary objective as a consequence coming out of SESAR is we are further doubling down on trying to convert the remaining off-label users of sevoflurane that we still have to our own drug. Of course, we knew that SESAR was coming. We did not know the results. In anticipation, we launched a dedicated sales push effort already a month ago to accelerate the conversion from off-label use to isoflurane, which has been and continues to be quite successful across our main markets.
Secondly, and that's also very important, we are also fully prepared to be very close to our customers over the coming days and weeks to avoid any negative spillover effects. As we have seen yesterday, misunderstandings happen very easily, and we need to handle those. The one thing that I would say, though, a stock market reaction is not at all the same thing as a clinician's reaction. No physician will make treatment decisions based on the share price. Much rather, they will rely on their own experience and, of course, the clinical data that they see. Let's move to the next slide, please, and look at some facts and numbers. First of all, in all countries where we operate today, isoflurane is available on the market. 97% or soon 98% of our business comes from countries where we even have our own Sedaconda isoflurane approved.
The availability of isoflurane does not stand in the way of a further conversion from remaining off-label sevoflurane use to isoflurane, and ideally, of course, our isoflurane. Let's look at how many of our customers are still off-label sevoflurane users. Again, to be clear, Sedana Medical does not sell sevoflurane. What happens in these cases is that customers buy our delivery device, the Sedaconda ACD, and then use sevoflurane, which is approved for use in the operating theater off-label instead of isoflurane. Of course, you could ask the question, why does that happen in the first place? What makes a customer use sevoflurane off-label? The explanation can mostly be found in the operating room.
In the operating room, sevoflurane, not least due to good marketing back in the days, pretty much replaced isoflurane based on slightly shorter wake-up times and the belief that if you save a few minutes in a surgery, you can squeeze one more surgery into a day. In some hospitals, when it was still used off-label, sevoflurane was simply more easily accessible to ICU staff, or you have anesthesiologists in charge of ICUs that were more used to sevo than iso. There's no approval and also no clinical data supporting that sevoflurane would be preferential over isoflurane in an ICU setting. In our main markets, you can see that most of our customers use isoflurane. The right drug, in our view, in Germany, it is approximately 85% isoflurane. In Spain, it's almost 100% isoflurane. It's only less than a handful of customers using sevo. U.K. is 100% isoflurane.
The one key market that has historically come from 100% sevoflurane, so has been a sevoflurane market traditionally, is France. The conversion is ongoing also there. We are by now up to 40% of customers using isoflurane. That conversion is actually accelerating. We've had a good number of also SESAR clinical trial sites that have already switched away from sevoflurane to isoflurane. There is more sevoflurane use in some of our distributor markets, which is the smallest part of our business. Also in these markets, ICU teams do have access to isoflurane. Overall, less than 20% of our ICUs still use off-label sevoflurane. Out of those, we estimate around between 10%-15% of patients fall into the SESAR category of patients, so moderate to severe ARDS patients. The next page, please. What will we do with all of this?
As I've already mentioned, the goal of converting off-label users to isoflurane is not new. We have had a dedicated sales push effort ongoing for several months and have seen good success with it. We will now double down on that and further intensify that, of course. We were quick to act upon the publication yesterday. A medical reply is already in place for all customers that could have questions or concerns. Also, the field teams are already trained to handle any questions effectively and be even more successful in switching people over to our own drug. A slightly more nuanced view on how we are thinking about the opportunities and risks by customer segment.
If we start with the vast majority of our customers today, so ICU teams that are using the Sedaconda system with isoflurane, these are people that have seen the patient benefits in action every day. In most cases, over a longer period of time, most likely they will feel confirmed that they are doing the right thing with the SESAR results. We will continue to work closely with them, of course, and make sure we cover all potential questions that come up, for example, reassuring them that long-term use of isoflurane is safe, as Peter has just shown based on all the data that we have. For example, we also had a large share of ARDS patients in our European trial with well-known positive results. What SESAR has found with regards to sevoflurane does not apply to isoflurane.
We will have a special focus on customers that are buying our device today but are using sevoflurane off-label. What we want to avoid here is that they see the SESAR study and say, "Okay, for these severe ARDS patients, maybe I'm switching back to intravenous sedation." We have a big opportunity here to convince them of the benefits of isoflurane. We'll focus on converting as many as possible. The switch is typically not such a difficult sell because isoflurane is cheaper than sevoflurane. Plus, sevoflurane requires higher doses. Customers have to buy more accessories like syringes, more scavenging filters, etc., which then also leads to a little bit more work as you need to switch the syringe less frequently.
When it comes to new customers, you might have a concern that it might become trickier to start new customers who are maybe not as well informed or have doubts because of the SESAR results. The first thing to note here, virtually all new customers that we start with isoflurane. I'm actually not aware of almost any case where a new hospital chooses to start inhaled sedation with sevoflurane today. Of course, we are promoting 100% isoflurane because that is our drug. Secondly, the process of starting a new account is quite lengthy. It is usually not a spontaneous decision. Today, I will try inhaled sedation. By the time a new account goes live, we have usually already spent several months with them, discussed clinical trial data, spent a lot of time training the teams, establishing protocols, planning the first patients, managing expectations, and so forth.
By the time they start, they have become inhaled sedation experts. In this process, we will have plenty of opportunities for education and explaining the difference between isoflurane and sevoflurane, for example, that important aspect of metabolism that Peter showed, that sevoflurane or 25 times more sevoflurane stays in the body as compared to isoflurane. What will be the overall effect of all of this? As always in life, it will be a little bit of a mix. We might have some customers where the SESAR news leads to a situation where they consider switching to IV, so intravenous sedation for some ARDS patients. On the other hand, we will have customers where we will see an increase in sales as a consequence of switching them over.
Based on our data, it's actually quite interesting that we typically see a sales increase after a hospital has switched from sevoflurane to isoflurane that goes beyond just the drug sales. Partly, that is because they see better outcomes. Partly, it is because inhaled sedation becomes cheaper. Sevoflurane is more expensive than isoflurane, as I said. Partly, it's because it is easier to handle with less frequent syringe changes and so forth. On the next page, everything that we can see now, we do not foresee a significant change to our outlook. We also leave our financial guidance, our financial target for the year unchanged. We had guided to reach positive low to mid-single digit EBITDA for our ex-U.S. business, and that still holds. Before we take your question, let me close on the next page with the three main reasons to believe in Sedana Medical.
Number one, and maybe most importantly, we have a therapy that has proven clinical benefits for patients and also proven health economic benefits for hospitals. We have just seen a deep dive into that from Peter. That is really at the core of Sedana Medical. If executed right, good medicine will eventually turn into good business. We have a core business mostly in Europe, which is growing. It has reached a new all-time high in sales in 2024, surpassing the COVID period, which was, of course, exceptional. We showed ex-U.S. profitability in two quarters last year. As I said, we are committed to deliver a full-year profitable EBITDA ex-U.S. this year. A growing core business that will start generating cash as of this year. Lastly, we have completed two clinical trials in the U.S. with positive high-level results.
We have a fast-track designation in place by FDA. We are on our way to a potential approval in a market that has three times the potential, the addressable market compared to the markets where we operate today. With this, thank you for listening. Let me close here and take your questions.
Thank you so much for the presentation here. As you mentioned, we will now carry on with the Q&A. As I mentioned in the start, if you are calling in and want to ask a question, please press star nine to raise your hand and then star six to unmute yourself when it is your turn. The first caller here that got the word is Filip Wiberg from Pareto.
Hi. Can you hear me good?
Yes. Hi, Filip.
Hi. Hi. Thanks. Yes, I have got a few questions, but I will take them one by one.
Perhaps firstly, previously, all the talk has been around the benefits of inhaled sedatives as a class over currently intravenous sedatives. It just seems like you're changing the story a bit now to only include isoflurane but exclude sevoflurane. Is that really fair to do? Or is it because of this new kidney damage data that you've seen? Yeah.
Let Peter answer that in just a second. I want to clarify one thing. The only drug we have approved is isoflurane. That comes with an obligation on us to only promote isoflurane. By law, we are not allowed to promote the benefits of inhaled sedation. We have to promote the benefits of isoflurane because that's where we have the clinical data. That has been very consistently the communication towards customers.
It is also fair to say that the thinking has evolved and the knowledge has evolved when it comes to the understanding of the differences between ISO and SEVO. I think, Peter, you are the best to comment on that.
No, yes, certainly. I mean, if you look at medicine and research in medicine, I mean, it is a responsibility to how medicine evolves based on evidence. We, of course, are sensitive to that. Our hope at the time when the SESAR study was being planned was that the results would be in line with the results that the same investigators found in a smaller study. There could have been a situation where the therapy was shown to be beneficial for this patient group. That is what they themselves hoped for. The fact that it is not tells us that it should not be used.
Additionally, in parallel with this emerging data that's been sort of the renal aspects have been emerging in the last few years, we now also see other aspects. As Johannes was alluding to, we have an approval for isoflurane. Both medically and regulatory-wise, that's our responsibility. I mean, this is not about being opportunistic. It's about helping patients. I mean, we're here to help patients. Of course, there's a business behind it. It would be highly responsible to sort of stick to old messaging if that's going to harm patients. As a class, you could say inhaled sedation, yes, that is different. Some would say, if you say isoflurane sedation to someone who's never seen that device, it may say less than saying inhaled sedation with isoflurane. I think that's how the appropriate wording would be.
I think as we move forward, it is inhaled sedation with isoflurane. It appears to be safe, and it appears to be beneficial for patients. I cannot say the same about sevoflurane.
Okay. Just looking at a website, for instance, and the instructions for the device, it's regarding inhaled sedation and also regarding the NICE recommendation that you have. It's for volatile anesthetics, which includes both sevoflurane and isoflurane. NICE, they did not seem to make a distinction about that. Could that change going forward? Is that what you're saying as well?
Absolutely. I will tell you that if you ask a lot of, and this is part of our educational effort as we move forward, is that for many anesthesiologists and non-anesthesiologists, volatile anesthetics have been considered to be a class.
There are certainly class effects if you look at the mechanisms of anesthesia, but they have different potencies. They have different toxicities. If I was to say inhaled sedation and ask someone if they'd like to have halothane or metoxyflurane, they would definitely not want to have that. There is even a study from Canada that was published some years ago where the authors did not distinguish between the use of isoflurane and sevoflurane. I mean, this is emerging data. It is important for us to help users, healthcare professionals, to understand these differences. We are the only company that's really driving this. I see that as our responsibility, if that makes sense.
The one nuance to add to that, Filip, and I'll admit that Sedana is very special in that case. You know that we have a history of a period where only the device was approved.
That was approved as a pure delivery device. That approval was actually for isoflurane and sevoflurane. That was agnostic of which one. At the time, both of these substances were not approved for use in the ICU. The approval for isoflurane was essentially transitioning that business from off-label use to on-label use. The only thing that was on-label then was isoflurane. You had a device that was originally a delivery device for two different agents, but then only one of those actually got approved. Since you mentioned the NICE guidance, the NICE guidance was issued before MHRA approved isoflurane in the U.K. That is still from that time where we only had the delivery device approved and not yet the drug. Since we have the drug approved, our full focus is and has to be on isoflurane.
Yeah. Okay. Thanks.
Still, it's kind of hard grasping the vast difference in results compared to what we've seen before, even for sevoflurane, which has actually demonstrated to be quite beneficial over propofol as well. Yeah, it has higher metabolism than isoflurane, but it still has quite a bit lower metabolism than propofol, right? It's still quite hard to understand why it performed worse than propofol. Do you have any further comments on this?
Yeah. When I refer to metabolism, I'm thinking about the volatile anesthetics. I had the privilege of using this device when it was still a prototype, the first studies with this device back in 2001.
The head of the department at the Karolinska Anesthesia recommended that we not use sevo, which was then very popular, but use isoflurane for the very reason I mentioned that volatile anesthetics' toxicities seem to be very closely linked to their degree of metabolism. Metabolism per se does not have to be harmful. For example, we're not aware that the metabolism of propofol, for example, leads to any toxicity per se, whereas certain other drugs do have sort of toxicity. If you think about paracetamol, for example, the toxicity of paracetamol is related. If you take an overdose, that's related to the metabolism and metabolic end products. So it's the metabolism of propofol. The challenge there that we don't have with any of the volatiles is that even though there is metabolism, you do not need the metabolism to eliminate the drug.
With propofol, midazolam, opioids, they all need to be metabolized to be eliminated, whereas volatiles as a group can be exhaled. In parallel with that exhalation, there is also a degree of metabolism. That is where this correlation between metabolism and toxicity seems to hold true since 2001. Hope that makes sense.
Yeah. To some degree. I think what I mean is that my point was that you still exhale sevoflurane. That should have a benefit over propofol, which has to be metabolized to get it out of the body.
Yes. Yes. I would. Yes. Sorry, Filip. Just to explain, had they measured this study, just to explain, this study was not really a study of sedation. This was a study of sevoflurane as a pulmonary protecting drug. The way the patients were sedated, there were no real sedation endpoints.
There was a target of deep sedation first two days, and then there was supposed to be light. That was violated. There was no data. They were not looking at wake-up time. One of the nice things about volatile anesthetics and wake-up time, and that goes for sevoflurane also, is that this rapid elimination occurs regardless of renal function, regardless of hepatic function. Those were not endpoints in this study. That makes this study quite different from our studies that we're focusing on the sedative effects and how patients can benefit from them. Works effectively for all patients, reduces opioids, and leads to rapid wake-up and lucid state so you can mobilize patients. The SESAR study was looking at this as a golden bullet for pulmonary dysfunction in ARDS. That's what they demonstrated in their first study in 2017.
It was a completely different indication. As I alluded to previously, the dosing of sevoflurane is very unclear in this study. There was no measure of end-tidal concentration. There were no processed EEG measures of depth of sedation. Looking at the hemodynamics, looking at the RASS levels when applicable, the sedation levels, it appears that patients were very, very deeply sedated and receiving very high doses. I would say that's probably unfortunate and related to COVID-19 because it was virtually impossible for these investigators. They state that they had standardized training and so on, but there was no real face-to-face training. That's an integral part of what we do both commercially when we introduce this to new ICUs and what we've also done in all our studies.
In the U.S., we had run-in patients, and we had people on the ground in the ICU educating staff about how to dose this appropriately. It's a very potent drug. I think that's both for good and in the case where you don't get trained properly or you cannot be trained properly because of a pandemic, that could have been deleterious.
Yeah. Philip, you have to round up now. We have more people that want to ask a question here.
Yeah. I guess that's all right. Do I have time for one more or?
Yeah. You can do one last.
Okay. I'll take the one that is top priority then. Yep. Perhaps if you went over these safety data from the U.S. trial just very briefly, so it was hard to grasp everything, is it possible to just go through them again? Because I think that's quite interesting.
Do you have any seven-day mortality that was included in this trial, for instance?
Yes. I think what we can, I mean, obviously, when something like this comes up, we scrutinize what we have. As we mentioned in our press release yesterday, there is nothing in our clinical data that indicates that the findings in the SESAR study would be relevant for our trials. This slide you see are serious adverse events. That is the tip of the iceberg. It is typically what regulators will look at when it comes to provability of the therapy. The mild and moderate adverse events will typically lead to label information about precautions or about side effects, whereas the serious adverse events are really the aspect that authorities look at, regulatory bodies look at when they want to determine the safety profile of the drug.
Looking at the two studies, there's somewhat different reported adverse events, serious adverse events in the two studies. Even for the first study, despite a 1.2% higher serious adverse events in the isoflurane group, that's highly acceptable, such a difference for the safety reporting is open label. It's not like the blinded assessments. You'd expect a new therapy to be scrutinized and reported more frequently. In the second study, we saw a higher reporting for propofol. This may also be related to training. Some ICUs in the first study had initially misunderstood and believed that they were only to report adverse events for isoflurane. That might be one of the explanations why we see a different reporting pattern in the second study. This is reassuring.
I could just say that, I mean, we have data for our second study, for our first study that we're beginning to look at now. I can simply say that there are no concerns. I do not see any concerns when it comes to the issues related to the SESAR study. I mean, we haven't really shared any more granular results. I think that's about how much I can say at this stage, that we're not seeing the same things that were seen in the SESAR study. I hope that's helpful.
Thanks a lot. Just, Philip, since it sounds like we didn't answer all your questions, just feel free to reach out, right? We'll be happy to discuss those.
Yeah. Definitely. I will. Thanks.
Thank you so much for the questions here. We will now carry on with the next caller, who is Mattias Vadsten from SEB. You have the word.
Hi there. Can you hear me? Yep.
Loud and clear.
Good. I guess just to sum it up a little bit, so you think basically that the use of sevoflurane as opposed to, for example, isoflurane was the key cause of the weak results in this trial and not maybe how it was carried out or what is the main more important factor? Because I appreciate all of the considerations that you provide here. It's very interesting, but I guess you get my question.
It's a very, very good question. The authors of the paper themselves have been struggling to understand the reasons behind excess mortality and less ventilator-free days.
I think that at least based on the discussions we had yesterday evening with them and with a number of other experienced users of inhaled sedation, primarily isoflurane, I think that there was an unfortunate situation with COVID-19 and many of these sites being inexperienced. This is speculation that, as I say, I think there are many things that point in the direction of a lack of understanding and probably staff also being quite left alone with these very sick patients. There is so much going on, so it can be quite difficult to identify that the sedation is actually the problem. That is the one part. The other part that we know, and that is also evidence of data, is that sevoflurane does induce renal dysfunction. It happens after a couple of days, after three days.
I didn't show this slide, but there's a few elegant studies that demonstrate that this happens after two to three days. Even after 24 hours, there's this polyuria. That in itself makes patients more sensitive to sedatives because if they have a low blood volume, a hypovolemic situation, the sensitivity to volatiles and to any sedative is higher. Propofol has the same properties, but if you have a polyuria phase and you become hypovolemic, you'd be more sensitive to the therapy you're receiving. I think our speculation or our interpretation is that both of these things have mattered.
Thank you very much. The next question, with regards to what you were telling us about COVID, what is your take?
When you look at per site data in the material, we show quite similar results actually for both arms when you look at the largest site recruiting, I think it was 176 patients. Then you have two sites that are driving quite a big difference from propofol to sevoflurane. Just your take on that and if that can be related to COVID somehow or the discussion there.
Yes. That could also speak to the potential sort of training need for training or experience. We know this about our therapy. This is why we have mainly former ICU nurses in the sales force. In the U.S. , we had respiratory therapists. People who know this is not a pill that you take once a day. This is a therapy that you adjust continuously.
It is very sort of the analogy that was made by one of the leading investigators or key opinion leaders in the U.S. when we had our first patient. He spoke about benzodiazepines as the bus, propofol, dexmedetomidine as the sports car, and inhaled isoflurane as the Formula One. It is a very potent therapy. You can sedate someone really well, really quickly. You can also wake them up very quickly. You need to get appropriate training for this. I struggle to see how that could have been the case in the SESAR study considering COVID-19. As I said, this is not our study. It was not under our control. We do not see anything like this in the data we have from our clinical trials to date. That is, I would say, maybe unfortunate, that aspect.
Thanks. My next question relates to the trials that you are making or have made. Do you think you can show a sub-analysis of key outcomes for ARDS versus non-ARDS patients in your own isoflurane European trial?
Yes. Yes.
Also, to what extent the US trials can basically disprove what is suggested by SESAR? I am talking about, do you think you can show ventilator-free days, for example, in the US material? Yeah. That is the question.
You mean now or potentially? We have not shared any data publicly besides the high-level results. The data will be coming. I think all I can say comfortably today at this call is that we are not seeing anything anywhere in the same direction as in the SESAR study. I think that is about how much I am allowed to say.
What I can tell you is that we did a sub-analysis that's been published, Becher et al. It's been published on patients with acute hypoxemic respiratory failure. That was a subgroup we looked at from the Sedaconda study. That is published. In that study, there were no differences in ventilator-free days or in any other relevant parameters between the isoflurane and the propofol group. That was about half of the patients that had acute hypoxic respiratory failure. It's the oxygenation part of the definition of ARDS. You don't have to do an X-ray. We didn't have X-rays planned for the study in itself. We chose to only look at the oxygenation and define that group, acute hypoxic respiratory failure. As I mentioned, we have published data on that that did not demonstrate any differences between the groups. As for the U.S. study.
Okay. Good. Yeah. Sorry. Please.
Yeah. I guess one question I also had was to what extent is inhaled sedation with isoflurane used today for patients with ARDS? Because I think it's a fairly large part of the patient population. I guess to a large extent, and if you can share any feedback that you received from customers in these use cases, really, do they see these tendencies of the therapy or at all?
Yes. Our meeting we had yesterday was with about 25 different physicians, of which some, of course, use this for ARDS patients. The comment from people who use isoflurane in these last days since the SESAR was published is, I mean, a lot of people are questioning why they did things the way they did, meaning in the deep sedation that they provided, the paralysis that was quite extended compared to recommendations.
Also looking at these aspects that I've mentioned already, the dosing of sevoflurane, which is not reported but indicators of over-sedation in the data. There is also the question, why did they use sevo? The explanation, as I said, is that the investigator is driving the study and wanted to repeat findings from a previous study. That previous study with sevoflurane was a 48-hour study. It may be that it may be. I mean, there may very well be some pulmonary benefits. I mean, the elegant study is looking at animals, looking at humans, this study from 2017 where sevoflurane had an anti-inflammatory effect. They stopped at 48 hours. This was one single-site study. They had control over the training. They had control over the exposure. They used processed EEG to keep patients appropriately sedated.
They didn't see the problems that this multisite study saw. I mean, 30 sites plus in the middle of COVID. There's no way that one investigator from one hospital can impact the way a nurse is now administering sedation in the trial on the other end of France. This is a challenge in general with taking a single-site study and doing it as a multisite study that you may gain numbers, but you may lose quality. That's a known fact in ICU research, actually. I think that those people who have commented have sort of, some have said, of course, Iso is the drug to use. Of course, there is, as we're saying, there is need to educate those who are not aware that there could be differences. I mean, that's part of our job.
Yeah. We now have to carry on again with the next one.
Then one final question from me, I guess. You talked a little bit about reiterating the outlook based on the news. Maybe is there a less likely that you will reach those targets now or else equal? And also, I guess the share price implicates a bit of a cut to the chances of U.S. approval. Maybe if you can cover this, what are the key considerations to make when you think about the U.S. approval based on this news? That's my last one. Thank you very much for the presentation.
Yeah. No. Thanks, Mattias. Of course, the same goes for you. If there's more questions, you know where to find us. Are we less confident with our guidance? No. Otherwise, we wouldn't have reiterated it.
As I said, what we're expecting is a mix of in some accounts, we will use the opportunity to grow our business. In others, we might lose a little bit. Overall, from everything that we, and it is, of course, very early days, but from everything that we can see today, we're still confident that we will continue our growth in our core markets. That will be sufficient to deliver the positive EBITDA ex-U.S. that we have promised. That is still what we want to be measured by. Of course, we will have to be very, very close over the next days and weeks to see the progress, have a very close eye on all the important indicators, whether we are right with that assumption or whether we have to course correct.
From all I can say now is we stand by our targets, and we're still confident to reach them. When it comes to U.S. approval, again, the share price, I don't think influences our chances of getting U.S. approval. Of course, I understand the nervousness every time there's data that are somehow related to inhaled sedation. Those are not purely positive. Of course, you can have ideas of does that somehow impact the risk profile of the U.S. trial or the U.S. approval. All I can say is that the whole US program is based on isoflurane. We actually have an advantage in the U.S. because we do not have this unique European situation where the device and the drug are separate and you're allowing for, or historically, off-label sales has grown in the U.S.
It will be a drug-device combination consisting of our delivery device, the ACD, and isoflurane. There is not going to be off-label use as much as we have historically seen it in Europe. When it comes to the chances of probability, the FDA will, of course, look at the trials we have run. We know already that the high-level results are positive. We met the primary endpoints in the main analysis and all supplementary and sensitivity analysis. Safety looks good, as Peter just showed today. We will get more data over the coming time. Nothing, as Peter said so far, indicates that we see anything that is close to what the SESAR trial has shown on the opposite. The confidence level for both the commercial outlook in Europe and the approval in the U.S. is unchanged.
Thank you so much.
Thank you very much.
We only have time for one more caller here today. That is Oskar Bergman from Redeye. You have the word.
Hi, guys. All right. Perfect. I got a few short questions. From my understanding, many years ago, you decided on the use of isoflurane in your European trial and the regulatory processes because it had a friendlier side effect profile compared to sevoflurane that was also looked into. Considering this, Peter Sackey commented in the start of the SESAR study back in 2020 that it is of minor importance if the study is conducted using sevoflurane and not isoflurane. They do not really age well. Just wondering why was this said if you knew that you yourself decided on isoflurane over sevoflurane because of its drawdowns?
Yes. Happy to answer that question.
Had this been a big investment from a Sedana's perspective, I think we wouldn't have chosen sevoflurane. I was in conversations with Matthieu Jabaudon back in the day that, "ISO, why wouldn't you want to do ISO?" This is completely up to the investigator. Our decision was only whether we should support the study or not. As I mentioned, in 2017, there was a publication in The Blue Journal in the American Respiratory Medicine that demonstrated improved oxygenation in a small study. This was only 50 patients, improved oxygenation, less inflammatory markers in blood, less inflammatory markers in bronchoal veolar lavage. It all sounded very promising. Matthieu Jabaudon and Jean-Michel Constantin were very eager to stick to sevoflurane. The protocol for the new study implied seven days of treatment.
The protocol initially stated that the concentration of gas was going to be measured, and they did not. I mean, there have been a number of circumstances that have changed what was initially a promising case into something that was not so promising and actually even harmful. I think that the take we had at Sedana at the time was, "Yes, we should support this because it is inhaled sedation. We're not aware of any huge differences." When we went for isoflurane, I was actually not working at Sedana at the time. There was a conclusion that at the time, the non-clinical data was not sufficient for sevoflurane to be approved with only a clinical trial. Sedana was tiny and was sort of very conscious about not investing in the way we have done for the US. That was, of course, favorable.
The established use of isoflurane in Germany also informed that decision. Isoflurane has been the drug that's been used ever since the early days of the ACD in Germany. BfArM were more keen to accept one single pivotal study and no animal data with isoflurane. Had this gone well, there could have been a scenario where sevoflurane had been where Sedana had looked into what data were collected, had interactions with regulatory bodies, and considered registering sevoflurane specifically for ARDS. Obviously, that's not the case. That's not where we are today.
All right. Okay. You listed three reasons as likely contributors for how the trial showed these results. I mean, they are all, of course, guesses and not necessarily fact. We cannot know.
What I think is interesting going forward is if you will be able to look into how ARDS patients in your European trial and US trials responded to treatment and return with an analysis of that. A short follow-up, what proportion of patients do you suspect in these trials would be ARDS patients?
Yes. As I mentioned, there is already a publication looking at about half the population that fulfilled ARDS criteria with regard to gas exchange. There was neither safety concern nor was there any clear difference in favor of isoflurane in that study looking purely at those hard endpoints. We will be doing a number of sub-analyses both in the single individual US studies but also in the pooled data. We will learn more about subgroups.
We also have a sub-study that's ongoing looking at patients with ARDS that's led by one of our investigators looking at biomarkers, etc. We will know more about this very subpopulation. We should remember, this is sevoflurane in the sickest of sick patients with acute respiratory syndrome that were in the study. I would certainly not generalize this finding neither to isoflurane nor to the entire ICU population, especially not with a seven-day exposure in a high dose such as it appears to have been in the SESAR study.
Okay. Thanks. Just a final question then. We know that roughly 25-30% of mechanically ventilated patients, they suffer from ARDS. Is it a fair assessment that it's the same portion of patients undergoing treatment today with your solution?
I mean, as Peter said before, in the SESAR population, you had moderate to severe ARDS.
Our estimate, as we had on one of the slides, is that the SESAR population represents somewhere between 10-15% of the mechanically ventilated patients in the ICU. Again, that population, we do not have any concerns with isoflurane. We do not have any concerns for long-term use. We do not have any concerns in that specific patient population. Commercially, it will be very important as we stay very close to our customers here to convert those ICU teams that are still using sevoflurane off-label. I might now have questions around that 10-15% patient segment. The best way, in our view, is, of course, to convert them to isoflurane, which is the approved drug and the only approved drug for these patients when it comes to inhaled sedation.
All right. Okay. Thanks.
Thank you so much. That was all the questions we had time for today. Johannes, you want to say some last words before we close here?
Yeah. No, thank you very much for the discussion, all the good questions. We will have a look at questions that were submitted on top of what we could answer today. If there's anything that we could not cover now in this good hour, we will find a way to get your responses on those as well. Thank you very much for taking the time. You have a nice day.