Hello and welcome to today's webcast with Sedana Medical, where CEO Johannes Doll and CMO Peter Sackey will present the U.S. clinical trial secondary endpoint results. If you're calling in and want to ask questions during the Q&A, to raise your hand, you press star nine and then star six to unmute yourself when handed the word. You can also send in questions via the form to the right. With that said, I hand over the word to you guys.
Thank you and welcome to our call today. Let's jump right in on page three, please. I believe Sedana Medical is at one of the most exciting points in our history this year with three key assets or three key cornerstones that we see as the foundation for future success and value creation. At the heart of it all is, of course, our therapy, a therapy that truly makes a difference for intensive care patients. One of the great privileges of my job is speaking with ICU doctors and nurses from around the world at a quite regular basis. Time and time again, they share stories of how inhaled sedation with isoflurane helps patients wake up fast, recover quickly, connect with their family sooner, and ultimately leave the ICU earlier. We are not just talking about a handful of cases here.
Several hundred thousand patients have been treated using our therapy across well over a thousand ICUs globally. We are building on a strong base of clinical evidence that shows real patient benefits, and on top of that, also compelling health economic benefits. Hospitals can actually save money using our therapy. Based on this, we have an existing business already in place, which is primarily focused in Europe today. Since the COVID-19 pandemic, we've delivered consistent growth. In 2024, we've hit a new all-time high in sales, and we didn't stop there. Q1 of this year was our best quarter so far, and we've also reached profitability in our ex-U.S. business, delivering an +8% EBITDA and generating positive operating cash flow as well. The third and biggest growth opportunity is the United States.
We are now getting closer and closer to entering what could potentially be a step change in our growth trajectory. Now, the main results from our Inspire studies are public, and Peter will walk you through them in just a minute. With these results combined with our fast track designation and an FDA-approved early access program and dossier preparations that remain fully on track, I feel we are well on track, and our goal is still to submit our application for marketing authorization in the early part of next year. If we move to the next slide, there's no doubt the U.S. is our largest growth opportunity. More than 2 million mechanically ventilated patients are treated in U.S. adult ICUs every year. That translates into an addressable market for U.S. of roughly SEK 10 billion-12 billion, so roughly $1 billion.
That's about three times larger than the combined opportunity in the countries where we are currently operating in: more ICU beds, more ventilated patients, and also a medical practice that tends to intubate more often than in Europe. Importantly, that $1 billion estimate assumes no price premium in the U.S. That's a conservative view becaU.S.e, as you know, medical devices and sedatives typically carry a higher price in the U.S. than in Europe. How should we think about the value of this U.S. opportunity? It comes down to three things: the size of the addressable market, the likelihood of approval, and our future market penetration. First, the market, as I've already mentioned here, around $1 billion with upside potential from pricing, as I just said. Second, the likelihood of approval based on the data we've now received. We believe that probability has further increased.
We met the primary endpoint. We saw no unexpected safety issues, and all other endpoints were either in our favor or showed no difference. Of course, there's never a guarantee. The decision rests entirely with the FDA, but on the clinical data side, we don't see any showstoppers. The market penetration will depend on the label we receive and, of course, on the strength of our commercial execution post-launch. We believe our data supports a label that is similar to what we already have in Europe, which would give us some good differentiators, such as, for example, a meaningful reduction in opioid use. We are in a strong position to reinforce our case even more with pooled data from Europe coming in and planned further analysis.
With that said, I'll hand over to the main act today, and Peter will take you through the data in a bit more detail.
Thanks, Johannes. Move to the next slide, please. As you may know, we've conducted the two INSPiRE-ICU trials across 30 ICUs in the U.S., enrolling 555 patients, of which 470 were randomized. The rest were run-in patients. Next slide, please. We completed enrollment last May, so a little bit more than a year ago. The primary endpoint in these identical design trials was the proportion or percentage of time at target sedation level assessed with the Richmond Agitation-Sedation Scale. The key secondary endpoints were opioid reduction during sedation, which was the most important and most likely, we believed. Second was time to wake up after sedation, time to reach RASS 0, meaning awake and alert or higher. Cognitive recovery after sedation, looking at the CAM-ICU-7, 60 minutes after end of treatment. Finally, the proportion of time which pertains to breathing.
These endpoints were designed with so-called sequential testing, meaning that if you meet the first endpoint statistically, then you can move on and analyze the second one and consider it to be something you could make a claim of, and the third and the fourth and so on. Should you fail to show that the first key segment point was statistically significant, the difference in favor of aspirin, you could not go further. We chose the order of these tests, these different variables based on the likelihood and the importance of the endpoint. Move over to the next slide, please. We presented the results at a meeting recently here in Stockholm where we gathered the most important contributors from the U.S., the principal investigators from the study sites, and we walked through the results in the two trials. We are going to share what we posted on clinicaltrials.gov now.
Move to the next slide, please. We have submitted data to clinicaltrials.gov where the study was registered, and according to their requirements, data should be entered within one year of study completion. These data were recently entered, and we saw them uploaded online just the other day. They are still in QC review, but based on their availability to the public, we felt it was important to share our interpretation of the data and what we believe they mean already now. This means that if you go to the clinicaltrials.gov site, you'll see a lot of queries. These are related to the format and the way we've presented the patient groups. These are being reviewed, and there will be some small changes, but not to the actual data on clinicaltrials.gov.
I think it's important to mention that what you see on clinicaltrials.gov are not yet peer-reviewed data. They're QC'd and according to the statistical analysis plan, so we believe in them, but there hasn't been any peer review. The results do not guarantee regulatory approval per se, and they may be revised for publication if the editor of the journal or the peer review process leads to requirements or requests of data to be presented in another manner. The same goes for the FDA. They may ask us to do the analysis of the data in another way, in subgroups or stratification and so on, and that may lead to minor changes. In essence, I believe that the data you can see there are the main results for these studies. Another thing to mention is that there are different populations, study populations that contribute to different analyses.
We have the so-called intent-to-treat population. That's all patients that have been randomized. The run-in patients are not included in that grouping. That is the most fair way to compare randomized study groups using the intent-to-treat population. We have the safety population, and that includes the run-in patients and all patients that received any study drug. This is to describe the safety profile of the drug when it comes to adverse events. Move over to the next slide, please. Now we're going to go through the results with you, what's been posted. These are from the clinicaltrials.gov, these tables. First, the percentage of time at target sedation level according to the RASS scale. In INSPiRE-ICU 1, non-inferiority was confirmed, and we did a number of sensitivity analyses and supplementary analyses to assess the robustness of the data.
All of these analyses demonstrated non-inferiority. Move to the next slide, please. The same goes for INSPiRE-ICU 2. The point estimates are slightly higher in both groups, but they are very similar if you compare isoflurane with propofol, the percentage of time between RASS -1 and -4, and non-inferiority confirmed in all analyses. We feel very confident that we have been able to demonstrate non-inferiority in this primary endpoint. Next slide, please. Looking at opioid dosing during sedation, our first key secondary endpoint, this was measured as the fentanyl equivalent dose versus baseline, standardizing all opioids into fentanyl equivalents. Looking at the change from baseline, what we saw was, and this is what we were hoping for, that isoflurane would be able to demonstrate the reduction of opioids versus baseline that was greater than the propofol potential reduction or potential increase.
That was the case both for INSPiRE-ICU 1 and INSPiRE-ICU 2. Transforming the reduction in fentanyl equivalents into percent reduction from baseline, INSPiRE-ICU 1 showed a 31% reduction of opioid dosing in fentanyl equivalents per hour versus baseline, and INSPiRE-ICU 2, a reduction of 37% versus baseline. This is to be compared with a 29% reduction or difference between isoflurane and propofol in the Sedaconda study, SED 001. Quite consistent reductions if you consider propofol during sedation to be similar to the baseline. You could say that it is around, it appears that in adults, it is about 30% dose reduction of opioids using isoflurane versus propofol. Next slide, please. Now we come to time to wake up after sedation. This was the time from stopping study drug until patients reached the awake state of RASS 0 or higher, meaning being slightly distressed.
Looking at the values, you can see they're low in both groups, in both studies. The median values are slightly lower for isoflurane compared to propofol. I think what's worth noting here is that in the two studies, isoflurane performs very similarly with an interquartile range from low numbers up to 45 minutes in INSPiRE-ICU 1 and up to 50 minutes in INSPiRE-ICU 2. This, I would say, is consistent with all studies looking at wake-up after isoflurane sedation, meaning that the vast majority of patients have woken up within one hour. We'll come back a little bit to that when it comes to why this is important, even though there's no statistical significance in any of these two studies versus propofol. Next slide, please.
Looking at cognitive recovery 60 minutes after sedation, the CAM-ICU-7 tool was used, and we can see that in INSPiRE-ICU 1, the distribution of patients with regard to their cognitive function at 60 minutes is in favor of isoflurane in INSPiRE-ICU 1 and in favor of propofol in INSPiRE-ICU 2. Once again, isoflurane is relatively consistent. If you look at the actual percentages of patients in the respective groups, you can see that about half of the patients are very lucid one hour after end of sedation, and about one quarter of them are fairly appropriate but have mild or moderate delirium. Then there is one quarter, 20% in the first study and 29% in the second, that have more delirium, significant delirium at one hour after.
In all, if you were to pull these data, you'd have almost identical values for isoflurane and propofol 60 minutes after sedation in this controlled design that the study implies. Next slide, please. Spontaneous breathing during sedation. This was a bit interesting, differences between the studies. In the first study, there was no difference, very similar values. Looking at assessments done every four hours, looking at spontaneous breathing efforts. In the second study, we could see a significant difference in favor of isoflurane, which is similar to what we found in the Sedaconda study. So higher proportion of time with spontaneous breathing efforts. Next slide, please. We had a number of other secondary and exploratory endpoints that I would like to highlight today that carry importance.
All of these outcomes, you could say, are classical endpoints in interventional studies in the ICU where you could say that they relate to safety in some aspect when it comes to sedative treatment. Let's look at the results from these endpoints. These were never sort of intended to be claims in our label. They are way beyond the key segment endpoints and not included in the multiplicity adjustment, but they're still valuable. They provide valuable information when it comes to the approvability of the therapy and the tolerability of the therapy. Now, looking at the ventilated three days, we can see that in INSPiRE-ICU 1, there was a difference of 2.1 days in favor of isoflurane. Looking at INSPiRE-ICU 2, the point estimate was the same for ventilated three days. Next slide, please. We have ICU three days.
Here we could see positive trends in both studies, not statistically significant, but a 1.7-day increase in ICU-free days in INSPiRE-ICU 1 and 0.6 ICU-free days more in INSPiRE-ICU 2. Both ventilated-free and ICU-free days are related to being alive and having the good outcome. Ventilated-free days implies that you are alive and off mechanical ventilation. ICU-free days means that you are alive and out of the ICU. It both has a patient-centered outcome, but also an ICU sort of health economic aspect. Next slide, please. Looking at the 30-day mortality, we could see that in both studies, there was a 5% difference in mortality at 30 days in favor of isoflurane, which, of course, is very reassuring. Some of you may remember the recent discussions that we had on the CESAR study using SED 001.
These results for aspirin contrast those results. We can move to the next slide, please. Looking at the three- and six-month mortality, similar to the 30-day mortality, there is a difference, not statistically significant, but clinically relevant, I would say, for both studies at both three months post-randomization and six months post-randomization, with 3% difference at six months in INSPiRE-ICU 1 and 10% difference at six months for INSPiRE-ICU 2. Next slide, please. Looking at the serious adverse events, which are the most important adverse events when it comes to the tolerability of a therapy, we could see a slightly higher percentage of patients in INSPiRE-ICU 1 with aspirin that had serious adverse events, but significantly lower percentage in INSPiRE-ICU 2.
Looking at the pooled results, overall, the percentage is lower for aspirin patients, which is very reassuring, I would say, for this new therapy in the U.S. setting. Next slide. Just a little bit about the first key segment endpoint, the one we chose to have as our first key segment endpoint in the sequential testing that is one way to manage multiplicity, sort of multiple testing. Opioids are used a lot in the ICU and actually used more and more over the last decade. One of the reasons is that physicians want to avoid the negative effects of intravenous sedatives. Analgo sedation has become something very popular in the last two decades, I would say. What has been found, though, is that opioids also have certain problems related to the dose. Some of them are well-known, for example, gut immobility and respiratory depression.
What is becoming more and more recognized is that opioids also contribute to delirium. In some recent studies, it was demonstrated that among patients receiving more than 24 hours of opioid infusions during mechanical ventilation, almost one-third of these patients suffered from opioid-associated withdrawal syndrome. This is well-known in pediatrics, but it is becoming more acknowledged also in adults. Importantly, there is also dose-dependent persistent opioid use. This has been demonstrated very elegantly in a very recent publication from Myers et al. looking at over 6,000 patients in Northern California that were receiving mechanical ventilation. They looked at the median hourly fentanyl dose and split the patients into four groups: no opioids, a little bit, a little bit more, and very high dose of opioids per hour, the fentanyl equivalent similar to what we demonstrated reduction of with aspirin.
They found that the higher median hourly fentanyl dose patients received, the more likely they were to have a filled opioid prescription after hospital discharge. This is in a cohort of 6,000 patients, non-surgical patients, meaning that there should not really be a sort of a surgical reason for them to need opioids after hospital discharge. About half of the patients had a filled opioid prescription after leaving the hospital. There is persistent opioid use, which was found in about 25% of these patients. This was also associated with a higher dose of opioids. This tells us that opioid dose is correlated. Opioid dose during mechanical ventilation, which is exactly what we have measured, is correlated with the higher likelihood of opioid use post-hospital discharge. I think this makes an opioid-reducing sedative very, very attractive. Next slide, please.
Summarizing the results, we've demonstrated non-inferiority for isoflurane with regard to percentage of time at target sedation level, a substantial opioid reduction in both of our trials, which is confirmed in our European trial and also in our pediatric trial. Non-significant, but clinically meaningful mortality differences in favor of isoflurane and positive trends for 30-day outcomes, including ICU-free days. ICU-free days were also higher in our German study in SED 001. That makes pooled analysis very interesting from a health economic perspective. That sort of beyond the label will be an important aspect of our work in implementing this in the U.S.
Finally, I would like to say that the U.S. Prescribing Information, the USPI, will be informed not only by the results from our individual studies, but also from the pooled results and also from current information for isoflurane and published studies. If we move to the next slide, the U.S. Prescribing Information for our therapy will be based on INSPiRE-ICU 1 and INSPiRE-ICU 2 from the pooled analysis of these two studies and the pooled analysis, including SED 001 that the FDA requested. Also, with the application we have, this 505(b)(2) application, we can leverage information from available publications. To date, there are over 200 publications on inhaled isoflurane for ICU sedation available. They tell more of the story than only our own studies.
Also, there is an existing aspirin label, which we are expected to follow to the extent where it is plausible that the same effects are valid also for ICU sedation. Also here, information in Canon will be leveraged in our application when it comes to the USPI. Finally, there are non-clinical studies that describe some features of aspirin that are not demonstrated or have not been analyzed in our own trials. These publications include pharmacological effects of both pharmacodynamics and pharmacokinetics of aspirin. There are many sources of information that will feed into our USPI draft. Next slide. Just to give some examples of information that we can draw from other documents than our own clinical studies and that may be considered for the USPI, supporting studies, for example, include patient categories that we did not include in our studies.
The reason we didn't include these patients in our studies, although we believe that they could benefit from aspirin, is that some of our endpoints, one, would not be measurable in these patients. For example, neurocritical care patients that need deep sedation might not be suited to target RASS -1 to -4, the same for post-cardiac arrest patients, status epilepticus patients, etc. These patient groups that are listed here are not excluded from our expanded access protocol, which indicates that the FDA do not see the lack of these patients in our own trials to imply that they could not be considered for inhaled sedation. Also, prolonged use beyond the study duration in our proposed trials. There are over 20 publications about patients receiving treatment for several days and weeks. And that information, we will also provide to the FDA and hope that that may impact our USPI positively.
Looking at the isoflurane USPI for anesthesia, there are some clinical effects described there, such as induction of and recovery from isoflurane anesthesia are rapid. This is information that needs to be rephrased if it's to be used for sedation, but we believe that the data that we have for our own therapy in our clinical trials and also in the supporting studies do support this statement for sedation. That, of course, remains; that will be an issue to discuss with the FDA if they agree with us, but we believe that we have data to support the same features for sedation as are known already for anesthesia in the last 40 years. There is a statement such as isoflurane undergoes minimal biotransformation in man. This sounds very complex, but what it really means is that isoflurane is not metabolized to any significant extent.
It's eliminated via exhalation, which, of course, means that you do not need to have good renal or hepatic function to eliminate the drug. Those are unique pharmacological features of isoflurane that we believe are part of the explanation behind the very short, rapid wake-up times. Next slide, please. What remains for us now to do when it comes to the U.S. and from a regulatory and medical perspective is to pool the data from the three studies and analyze them for our NDA, to complete the non-clinical parts of the dossier, put together these integrated summaries of efficacy and safety and the clinical overview, and draft the USPI and submit all these data together with all the other parts of the dossier in Q1 2026. In parallel, we'll be preparing the results for publication in peer-reviewed journals.
We're also working, as you know, on the Expanded Access Program for difficult-to-sedate patients, where we're currently working with the contracting and IRB aspects and hope to initiate in the fall. Next slide. The next slide is nothing. Questions, I guess, would be the next slide.
Thank you so much for the presentation here. As you mentioned, now we will carry on with questions. 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. The first question here is Philip Thureborn from Pareto Securities. You have the word.
Hi, can you hear me well?
Yes.
Great, thanks. I've got a few questions here, perhaps just starting with a general one. What were your expectations ahead of this in terms of statistical powers?
What were your expectations in terms of the endpoints that you expected to see significance? It was a lot about you placed these key ones in a sequential order with opioid usage in top, but did you have an expectation for all of them to meet statistical significance?
I would say we had hope for at least a couple or three, for sure. We have experience from wake-up times in our German study compared with propofol. The scenario where you run this type of clinical trial with closed titration of sedation with too early control of sedation depth is very far from daily practice. It implies much tighter control. Also, propofol is the most short-acting full-range sedative available. With daily wake-up tests, which are standard, and with the too early control of RASS, we were not very surprised to see that the differences were not so great.
The same applied actually for SED 001. I think that's one of the reasons why we did not place that as number one, even though we see that as a very strong sort of differentiator between aspirin and IV sedation. If you go out in the real world and you look at patients sedated with propofol, there are a significant proportion of patients that are sedated a little bit deeper than prescribed. That's actually the general pattern in the ICU that patients end up being deeper than intended. There's lots of literature on this. The proportion of these patients end up taking hours and sometimes even days to wake up.
I think that's the clinical reality if you interview an ICU physician, if they've had patients with propofol that don't wake up and they go for CT scans and they have neurology exams, etc., and then finally they wake up. That is the clinical reality. That's not what you see in our trials because they are very strictly controlled. This also means that it's harder for us in that context to show a difference. We do see short wake-up times. We do see that our therapy is very predictable in terms of waking up. There's always a small tail of patients that will not wake up because they have encephalopathy, sepsis, etc. That will always be the case. I'd still say that with our therapy, if you stop our therapy, the drug is out.
You know after one hour, after two hours that if the patient does not wake up, it's not the sedative that's causing it. With the other drugs, no ICU physician who sedated someone with propofol for a few days would feel competent to say that. They would end up going for different exams, which is an extra cost. It's an extra staffing resource and a risk for the patient. Every transport of an intubated ICU patient is a risk. Even though we can't make a claim that we are better than propofol in our trials, I believe that if we are able to have a label that's similar to our European label where we speak about patients waking up within 60 minutes typically, that's a kind of claim that resonates very well with clinicians.
If you say, "Here's an ICU sedative where you wake up within 60 minutes," typically because of the exhalation and the lack of need to metabolize the drug, that will resonate very well. Just to answer your question, opioids is something that we have seen in our previous studies, and we feel is very important because of sort of the negative effects of opioids. We are very happy that that endpoint came out. Had we seen a shorter wake-up time, we had not expected it to be massive, the difference based on what we know from our first German study. When it comes to CAM-ICU-7, sort of waking up and 60 minutes after end of sedation, I think we would have believed that we would have seen a difference in favor of isoflurane. Now we saw that in one study and not in the other study.
Overall, I think that the percentage of patients that are not cognitively sort of in the best shape is still very relatively low. It's about 20%-30%. We would have hoped that would have been significant, but it's not a deal breaker in our opinion. As I mentioned, all the other endpoints that you see listed on clinicaltrials.gov, they were not positioned to be able to form a claim unless there was a huge difference in both studies. They are not controlled with multiplicity management, which the four key secondary endpoints are with the sequential testing. They are important to inform sort of the decision to approve our therapy or not. The fact that we do better or similar to propofol is strength in our opinion.
We're very happy with, I'd say overall, we're very happy with the results, and we feel confident that we have a case when we work now with the dossier.
Okay. Just to make it clear, you think that the wake-up time for propofol in these trials here was significantly shorter than it is in the real world. Is that a correct interpretation?
Yes.
Okay. Thanks. It seems when you go through the results, it's quite a big difference in the results between the studies. If you look at the absolute values for the wake-up time, for instance, it differs quite a bit between the studies and also the p-values and all of that. Is that just random factors, or is there anything else to explain that?
That's a very good question.
We have a few different explanations for that, none of which are sort of we can draw super strong conclusions, but we had slightly different, so the ICUs obviously were different. We had a little bit more medical patients, medical ICUs, different PIs, different constellations of PIs, slightly different dosing. Propofol was dosed lower in the INSPiRE-ICU 2 study than it was in the INSPiRE-ICU 1 study. More surgical anesthesia ICUs in the first study than in the second study. Patient case mix was mainly medical, surgical. There was slightly more medical. It was a slight lag in, oops, can you still hear us? Hold on.
Yeah, now it's fine.
Something happened here. Going to turn off our Bluetooths here on our phones. Sorry. Yes. The INSPiRE-ICU 2, during the course of the studies, we had sort of training and retraining.
One of the things that we did retraining on when we had done about half of the patients in the first study, but less than a third in the second study, was related to how the information about the blinded RASS was relayed to the study teams, and sorry, from the study teams to the clinical bedside team. I think both the higher percentage of time at target in the second study and also the dosing and probably also the wake-up times in both groups, including the propofol group, was related to additional training about sort of strictly sticking to the protocol, relaying information from the blinded assessor to the clinical teams. This may have led to that they sort of performed better in general.
We know today that, sorry, IV sedation can work almost as good, I would say, as isoflurane sedation if you put a lot of effort to it. Ever since 2000 was the year when the daily wake-up test study published in the New England Journal of Medicine, John Kress demonstrated that if you do a daily stop of IV sedation, you cut the time on the vent by a few days, and you cut the time in the ICU by several days. That was in 2000. Since then, there have been multiple studies showing that if you give a lot of attention to the IV sedation you're giving, you keep on doing daily wake-up tests, you go for lighter sedation, etc., you do combined wake-up tests, breathing tests, you get better outcomes. These studies all are about managing the issues with accumulation of IV sedation.
In that first study in year 2000 for John Kress, they did not only look at benzodiazepines, they looked at propofol as well. They found the same effect when you compared the propofol group with patients that had daily wake-up versus those that did not. All of these efforts, if you spend a lot of time with your sedation with IV drugs, you could get relatively short wake-up times. That is not how the reality looks like today. It is really difficult to devote so much time to sedation. That is where I think isoflurane is a more forgiving drug. I think the supporting studies that are out there in the literature indicate that even when you sedate deeper, patients wake up quickly. I think I have that answer. I think they gave a lot of attention to the sedation aspect in the second study.
Yeah. Okay.
All right. I just wanted to stay on the wake-up time for a bit because opioid usage, all right, it's important. From a hospital perspective in the U.S., for you to be able to sell to them, they have to see a commercial case in that as well. They need to be able to save some money. Based on the NICE guidance that you have, the cost saving comes from waking up faster and getting out of the ICU in a quicker manner then. Do not you see this as a big issue then that you cannot show that it is significantly faster wake-up in this U.S. trial here?
The label has a section that is about the clinical trials where you compare the two therapies that have been tested in the study. There is also a part that is called the clinical pharmacology.
The clinical pharmacology section, that's where we currently have described the pharmacokinetics and pharmacodynamics of our therapy. In the European label, as I mentioned, we have a statement about typical wake-up time being within one hour. If we were to come anywhere near that in our US PI, I believe that the available data on isoflurane sedation, and that's not only our own studies, but other studies that have been performed looking at wake-up times, is quite compelling. When it comes to NICE guidelines, that's sort of related partly to the wake-up time, but also the downstream effects of those short wake-up times, meaning ICU free days. As I mentioned, if you look at the results from the Sedaconda study and from the two INSPiRE studies, you have roughly one ICU free day more with using isoflurane versus propofol.
I think if that's something that we can convert into a sort of health economic message, I think that that will also be compelling. If you go into an ICU and you say, "This is a therapy with which your patient will wake up within one hour, typically." If they do not, then you have reasons to believe that something else is going on with your patient. That is a message that will resonate better than talking about 30 minutes shorter time than with propofol because that's not the typical pattern when you use propofol, as I mentioned. This is hard to describe to a non-ICU physician or non-ICU nurse, but this is truly the case that the typical comment when someone does not wake up after four or five hours is, "Oh, she's old. She needs time." Or, "He's very sick.
He needs time. With our drug, I would say that's not the case. Now, that's not going to be in the label what I just said, but I think this waking up within one hour, if we have something about that in our label, I think that will be equally as strong as having a benefit of 20 or 30 minutes. We're not in the operating room. In the operating room, 20 or 30 minutes is huge. We're now talking about the reliability of wake-up, meaning that when you stop the drug, you know that the patient should wake up normally. That translates into progression of care in that you can plan the wake-up time. When you extubate a patient, you have a nurse, you have a respiratory therapist, you have the physician there. You need to be prepared to reintubate this patient.
If you have a therapy that consistently leads to patients waking up within one or two hours, you can assemble this team, and they know that they will have work to do, and this patient will be extubated. Once you have a drug or therapies that do not give that reliable wake-up time, you may end up a full day patient not waking up. What happens in the afternoon and evening when you only have one physician left in the ICU is that you resedate that patient, and then you wait one more day until you extubate them. Now I feel we're getting into a lot of sort of medical details about sort of the messaging around this therapy.
I don't believe that a one hour or 30 minutes mean value difference in wake-up time would be what would be most important when it comes to this endpoint. It would have been great if we would have seen that, but our expectations were not super high based on what we saw in SED 001. We're very happy that the majority of patients, so as I said, the interquartile range stretches up to 50 minutes in INSPiRE- ICU 2 and 45 minutes in INSPiRE- ICU 1. Those values in themselves, they have a strong message in my opinion.
Okay. Thanks for that. I'll limit myself to just one more question if that's all right. Just now you reported the study results for the separate trials. The question is more, what do you expect to see once you pull them together?
The statistical power will go up, so you believe this could tilt some of the endpoints where you have seen a trend where you could tilt them into statistical significance.
Yeah. When it comes to the label, I do not think very much will change because we have non-inferiority in both studies, and we had that in the SED 001 study. Those estimates, even if pooled, there will be no change. When it comes to opioids, we see a reduction in our German study. We see it in the two U.S. studies. Same thing applies there.
It will be more that there will be if we align with the FDA on pooled data being presented rather than individual studies in the label, then you'll simply have one estimate for opioid reduction in the label for the combined studies, either the two U.S. studies or the two U.S. studies plus the German study. It'll be somewhere in the range of 30%. That wouldn't change much. When it comes to wake-up times, as I was alluding to, the differences are very, very small. We did not make it in any of the studies to statistical significance. We don't expect that to be anything that will make it into the label. As I said, these are all review questions.
When it comes to the other endpoints, the long-term endpoints such as mortality, 30-day ICU free stay, ICU free stay days, ventilator free days, those endpoints are not analyzed with any multiplicity correction. We do not feel that we do not believe strongly that the FDA would say that we could now bring them into the label just because they became statistically significant. That is typically not what you would expect. We might get some information there related to safety, for example, maybe mortality, but that will be a review question whether the FDA agreed that that is an important safety variable to include in the label. I think it is rather on the other aspects of this sort of if you think about the information that we get from these studies, it is not only for the label. It is also for reimbursement, etc., market access.
There, I think that pooled data may carry greater significance.
Okay. You have not decided with the FDA whether the label will include pooled data or the separate study results?
No. That is exactly. That is a typical question that will be either during the pre-NDA meeting or in the review phase that we, depending on the guidance that we have read and the advice that we will get, will propose pooled data or separate study data. I mean, personally, I lean to pooled data because it is easier for a prescriber to read a point estimate that is based on a big cohort of patients than to look at two different study results and try to figure out which one should I believe my patient. That is my personal preference. It has to be the FDA need to agree with us that that would be an appropriate strategy.
Yeah.
Just a bit on that, Philip. I mean, there are two slightly separate or actually completely separate questions here, right? One is, are these data good enough to get approval? That is an FDA decision. I am sure in your model, when you look at Sedana Medical's value, it makes a huge difference whether there is a U.S. business or whether there is not a U.S. business. The second question is, based on these data, will we find enough hooks for differentiation so we can, together with good commercial execution, have a successful launch? For the first question, I think that the way the FDA would look at these data is, okay, primary endpoint met, safety in line with expectations, opioid reduction proven, everything else either trending in our favor or no difference.
From an FDA approval perspective, we do not see any showstoppers in these data, right? There is never a guarantee, but we feel quite confident that based on the clinical data, at least this therapy is approvable. The second question, will we find differentiation? I think this is where your question around pooled data and further analysis will be extremely relevant. The good news is when it comes to the more health economic arguments, here, it is not only dependent on the claims that you will be able to make in the label because you are dealing with purchasing organizations. You are dealing with purchasing departments in the hospital, and they are open to also look at something like the NICE guidance. They would look at European data.
I mean, if you just look at the ICU free days, now we had 1.7 days difference in one U.S. study, 0.6 in the other. We had 1.3 in the European one, also in our favor, and then 3.5 days difference in our favor in the post-hoc analysis. All of these go in our favor. If you imagine a publication that is pooling all of these data, that could make a quite convincing argument towards somebody who's making a purchasing decision in a hospital, even though the label maybe would not say you can expect your patient to leave the hospital X days earlier.
Okay. Yeah. Thanks. That's a very good answer. I'll stop there and let someone else ask some questions as well.
We'll now carry on with some questions that have been sent in to us. 470 patients randomized across both studies.
Any thoughts to be added regarding the amount of patients as basis for the secondary endpoint readouts?
Is this related to trying to figure out if this is related to sort of power? We have not performed power analysis looking at the 470 patients and the key secondary endpoints nor to the other endpoints. The individual studies were powered based on assumptions related to the primary endpoint. That answers the question.
Thank you. Do you think it is possible to show one-day reduction in ICU stay based on the data at hand today? How many ICU days are there in total to put into perspective here?
I think it will be too early to answer, but as I was alluding to, we do see that the ICU free days are more, even though not statistically significant, in all three studies, all three adult studies that we were discussing. I think that will be sort of a question related to what Johannes was describing from a reimbursement perspective, whether that is considered one ICU free day. In my opinion, it is a good outcome, one ICU free day, one day alive and outside the ICU. I think that would resonate well both with payers and with patients and families. That will remain to be seen whether they agree with us.
Yeah. I think there is, again, the question of statistical significance, and we will see what the pooling data shows us. There is also the relevance question, right?
We have now four data points, again, ICU 1, ICU 2, the European study, and the post-hoc analysis based on the European study, all pointing in the same direction that inhaled sedation with isoflurane is reducing the ICU length of stay, and you have more ICU free days. Just intuitively, even if it's one-day difference, that's a pretty meaningful outcome, first of all, financially, because every ICU patient costs a couple of thousand dollars every day. It's the most important or most expensive place in the hospital to treat a patient. If you can cut that down by one day, it makes a big difference. Also just intuitively, if you think about your now these patients have only been exposed to isoflurane for two days, right? Otherwise, they got propofol.
Only this two-day difference in change of sedative leads to a day in additional ICU free days. That is a quite meaningful outcome.
Thank you. What will be the price of Sedana's therapy versus standard of care in the U.S.?
Yeah. That question is too early to answer. What I can say is in Europe, we are priced a bit higher than the intravenous sedatives, the reason being that we also bring better patient outcomes. I'm expecting the same pattern in the U.S. as well, but it's too early to give a specific number.
Thank you. If we look at patients under the early access program, difficult to sedate patients, what share of the total amount of patients are those in the U.S.?
That's a good question.
The definition we have agreed upon with the FDA is a unique definition in that it's not a definition that is universal. There's no universal definition of difficult to sedate. That means that you can rely on available studies that describe the percentage of patients that are difficult to sedate in the studies that are available, not from the U.S. specifically, but from Europe. We are talking about somewhere in the range of 15%-25% of all mechanically ventilated patients. As I mentioned, this is related, that's based on a definition of, for example, the Spanish Association for Critical Care have their own definition, which is not too different, but it's not identical to the one we have.
Thank you.
Does this data impact your ambitions to launch in the U.S. or at least impacting your plans onto how to launch in the U.S.?
No. The strategy is still very intact. I think what has changed is that it is becoming a bit more real because the likelihood of the clinical data being approvable has increased because there is nothing that is going against us here. Again, we have a few things in our favor as well. We are continuing to prepare for a launch that is going to be focused on the great network that we already have in the clinical trial sites. We will use those as our lighthouse accounts and build sales territories around them.
I think the level of enthusiasm that we're getting, you saw a lot of happy faces on that picture that Peter was showing earlier, gives us the confidence that we have a good enough support network to start a successful launch ourselves.
Thank you. 267/5000 there. How does the failure to demonstrate a reduction in ICU stays affect for insurance companies' ability to include sedation among their treatments?
Yeah. I think we've covered that already. There is no failure of showing length of stay. There is a one-day difference that we see. Let's see how that changes when we pull the data and combine it with the European data. From a hospital purchasing perspective, that is a meaningful difference. I would not call that a failure.
Thank you. ICU free days differ slightly from the European study. Why do you think that is?
The data are actually quite close.
In Europe, we had 1.3 days difference. In the ICU free days for the U.S., we had 1.7 and 0.6 respectively. I think these results can be seen as quite consistent. There is also a post hoc analysis where the difference was greater, where we are comparing patients that were exposed to either propofol and isoflurane for a longer period of time. That explains the bigger difference here in terms of days. Importantly, all trends are in the same direction. It is actually very consistent results.
Thank you very much. Opioid misuse generally does not stem from patients being admitted to opioids intravenously at an ICU. Considering this, do you think the statistically significant data on the opioid secondary endpoint carries any weight from a commercial standpoint?
I beg to differ.
The biggest study examining this was the one I referred to, 6,000 patients in a very well-controlled data system, the Kaiser Permanente in Northern California, demonstrates a clear correlation between the dose of opioids in fentanyl equivalents given during mechanical ventilation and the likelihood of filling an opioid prescription after discharge and also of persistent opioid use in the first year. There is a clear correlation between what we do in terms of opioid use in the ICU and later misuse.
Thank you. Moving on to the last question here. Is the FDA Fast Track designation now at risk of being withdrawn considering no meaningful data could be statistically proven?
I beg to differ again. The primary endpoint has been demonstrated to sort of be within the primary endpoint.
The most important key secondary endpoint, opioid use, has been shown to be significantly lower in both studies and in line with previous studies, 50% reduction in the pediatric study, 29% reduction in our first study. I would say there's a really meaningful difference that we're happy to have found and that we believe strengthen the case for inhaled sedation.
Thank you so much. That was all the questions we had. Thank you so much for presenting here today and answering all questions. Thank you all for tuning in. I wish you a pleasant day.
Thank you.
Thanks a lot. Have a nice day.