Spectral Medical Inc.

and welcome to the Spectral Medical Inc. Investor Update presentation and conference call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Ali Mahdi. Thank you, Ali. You may begin.

Thank you, operator, and good afternoon, everyone, and thank you for joining us today for Spectral Medical's Corporate Update Conference Call. Joining me today are Chris Sito, Chief Executive Officer, Dr. John Kellum, Chief Medical Officer, and Blair McInnis, Chief Financial Officer of Spectral. If you have not seen the news release which was issued earlier today concerning a reminder for this call, please note that an updated presentation has been posted on Spectral's website. which will be used by management during today's call. Following management's presentation, we will conduct a Q&A session. Instructions will be provided at that time for you to join the queue for questions. Before we begin, we are required to provide the following statements regarding forward-looking information, which is made on behalf of Spectral Medical and all of its representatives on this call. Remarks and answers to your questions today may contain forward-looking information about future events or the company's future performance. This information is subject to risks and uncertainties that may cause actual events or results to differ materially. Any information regarding forward-looking statements is made as of the date of this call, and the company does not undertake to update any forward-looking statements. Please read the forward-looking statements and risk factors in the MD&A as these outline the material factors which could cause or would cause actual results to defer. The company will not provide guidance regarding future events during today's call. Management does not anticipate providing guidance in future quarterly or interim communications with investors. I'd like to turn the call over to Chris.

Thank you, Ali, and good afternoon, everyone. Today we're going to take you through a very detailed presentation on our plan to accelerate the pace of Tigris enrollment. First, I cannot underscore enough how well our business is positioned for regulatory and commercial success, but I want to acknowledge the frustration around the pace of Tigris enrollment. And so that's the million dollar question for me, for John, for Blair, for the Spectral team. What are you doing about it? And that is what our presentation today focuses on. How we are going to change the course of Tigris enrollment. So let's begin. Turning to slide five. We have a short recap on Spectral's transformative journey and how we have strengthened this business since the Euphrates trial outcome. We've consistently looked for opportunities to optimize the outcome for our PMX product, both on a clinical front and a commercialization front. In 2019, it was a fresh start for Spectral, with a de-risk Tigris trial design approved by the FDA. We also went through the development of SAMI, and in 2019, the FDA approval for its use in Tigris. This was a defensive measure so as to have a device in place that could run the PMX therapy and thus reduce trial execution hurdles. In 2020, we built the commercial foundation and entered into our exclusive distribution agreement with Baxter. We said back then that Baxter was the perfect commercialization partner, and that couldn't be more true today. In 2021 was a period of blocking and tackling. We brought on Dr. Kellam, a highly regarded clinician, and a leading world expert on sepsis to lead our clinical team. We also looked for ways to continue to optimize enrollment and received approval from the FDA to use SOFA for inclusion criteria, a tool that has resulted in inclusion of a significant number of our randomized TIGRS patients today. In 2022, we went through a period of repositioning. PMX was granted breakthrough device designation by the FDA, Additionally, the FDA approved the increase of an additional 10 sites, allowing for a total of 25 TIGRIS trial sites. We made this move as we recognized we needed more shots on net. And finally, in 2022, we refocused spectral resources on TIGRIS and entered into the iDialco transaction with InfoMed. Which brings us to today. Our plan to move TIGRIS forward focused on two key levers, increasing the number of sites And two, site productivity. Turning to slide six. This is a snapshot of where we are today. As of today, we're at 53 patients randomized, which is just over a third of the way through Tigris. In terms of number of sites open for enrollment, we have 16. We had two recent site additions, Medical University of South Carolina in January and University of California San Francisco in February. And both are very active and we're very pleased with how they're performing so far in the clinical trial. We have a number of trial sites in the pipeline with a path to 25 sites by the end of September of this year. Certainly, there's a question on why do we believe we can bring new sites on at this cadence. Our confidence around this is based on the work that was done in 2022 and that we are in clinical trial agreement phase or CTA phase with these pipeline sites. So basically, when we are at this stage, the site is committed and few, if any, drop out. But John will speak to that in more detail on additional sites and activities taken to build this pipeline later in the presentation. Turning to slide seven, which speaks to the challenges that we have faced in Tigris, but also speaks to the steps being taken to remove or mitigate these challenges. The key challenges that we have faced have resulted in a slower than anticipated enrollment rate. Community rates of sepsis certainly have played a role. as well as the mortality due to COVID of patients, which likely would have been suitable for TIGRIS. Clinical site staffing turnover and burnout continue to be issues in clinical research enterprises facing long recovery as a result of the pandemic. TIGRIS is on the complex side of the scale with respect to clinical trials, and less difficult trials will recover first from an enrollment perspective. Another of the key challenges is public trust and awareness of investigational devices and therapies. This has been an impediment on the informed consent side to enrollment, and this has created a difficult recruiting environment for us. They say misery loves company. We are not the only ICU trial that has struggled with enrollment post-COVID, but these are the cards we have been dealt and we have to find a way. So what are the steps being taken? The first is getting more shots on net, and that has to do with increasing the number of trial sites. The remainder is focused on site productivity. We have increased our trial resources internally. The iDIALCO transaction has allowed us to fully allocate our clinical team's focus on tigris. We have also taken some what we consider extraordinary moves, including transitioning to a new CRO, Beaufort, as well as embarking on a meaningful public and investigator education campaign. All of which John is going to get into deeper into detail later in the presentation. Turning to slide eight, pre-screening data or where are the patients? We've seen pretty robust pre-screening since mid-2022 with aggregate screening averaging anywhere from 50 to 100 patients per week. So in a typical week, we are seeing just over 100 patients with sepsis. and only converting anywhere from 0.5% to 1% of those screened into a randomized patient. This equates to an enrollment rate of approximately 0.18 patients per site per month, which is significantly lower than our assumptions when Tigris was initially launched. However, as a comparison, Euphrates' average enrollment rate was 0.136. So why is this conversion ratio of screened patients to randomization low? Well, We have a strict inclusion criteria combined with a recovering clinical research environment. However, these tight criteria benefit our mortality data and effect size. John, just quickly, can you discuss the waterfall chart on the right and certainly speak to perhaps some of the exclusion criteria buckets where we potentially have an ability to influence and improve site productivity?

Thanks, Chris. So the way to read this is that we start out with approximately 50 to 100 patients per week. That's the first bar on the far left. That's patients who meet the definition of sepsis. The majority of those actually meet the definition of septic shock, meaning that they have hypotension, they require vasopressors. But they don't require vasopressors at the dose that our protocol specifies. And this is selected way back in Euphrates, and it's really an indication for severe or some would say refractory septic shock, which is the definition of the clinical population that we're intending to study. But there's also another requirement, and that is that the patient hasn't been in this profound refractor septic shock for very long. So 30 hours is our limit. And so that vasopressor window bar reflects some patients that screen out because they've been on their vasopressors too long. Then there's an additional requirement that the patient has to also have other organ failure. This confirms the clinical condition of endotoxemic septic shock because it's associated with additional work and failure and you can see that additional patients are screened out from that criteria. And then we have exclusions. Exclusions such as end-stage kidney disease, underlying HIV, cancer, etc. Some of these clearly will not impact the use of the product once approved, but they do restrict the enrollment of patients into the clinical trial. And again, Because this trial is a confirmatory trial, and indeed it's an extraordinary confirmation because it uses a Bayesian statistical analysis that allows us to combine data from the prior trial, the enrollment criteria, including exclusion and inclusion criteria, have to be precise relative to the prior data. Then there's finally that large drop you see that goes from exclusions to non-survivability. Now, we always have patients who are this sick who are judged to have no chance of survival and you don't want to be enrolling patients like that in clinical trials. So normally speaking, almost all the patients who meet those criteria would be excluded. However, in this trial, we actually are including some patients who are judged to have a very poor survivability possibility, but that that's coming from septic shock. And if the reason that they're dying is septic shock, we encourage sites to go ahead and enroll those patients. Obviously, if this patient has a very poor prognosis because of underlying comorbidity, and just happens to have septic shock, then that's a different story. This is a little bit of a, and we'll talk more about this later, but this is a bit of a retraining, because normally speaking, you wouldn't enroll patients like this, you wouldn't even approach patients like this, for inclusion in the trial. You might think that it's giving families false hope, etc. But we've seen some remarkable turnarounds both in Euphrates and in Tigris such that we do encourage sites to enroll those patients. We lose some patients, about a third of the patients who get down to this level because of informed consent issues. Some of that is coming from just the fact that you can't identify a surrogate consentor, a family member, since the patient's usually too sick to provide their own consent. In fact, almost never are they able to provide their own consent when they have this disease process. So sometimes the family's just not available. Other times, the patients or the family just aren't willing to consent. I'll talk about this more too. I do find that this is more common in the post-COVID environment. There seems to be an underlying suspicion of medical research, which is something that we need to continue to address. And then finally, we have a screening criteria for EAA. And then there can be some logistical factors that enter in. We don't expect sites to enroll patients 24-7. We do expect them to enroll patients five days a week. It's late on a Friday night, and does the coordinator stay and enroll that patient? We think that's a modifiable, and that's something to talk about in a moment. This is where we end up with a relatively lean number of patients that meet all of these criteria.

Thanks, John. So just turning to slide nine, this is the spectrum of enrollment levers that we have considered. We considered a wide range of strategies to increase enrollment rates. However, each strategy needs to be weighed against any adverse impact on PMX's regulatory outcomes. I'll start with the middle bucket of increasing sites, as this is the biggest lever as it should be linear. Once again, the more sites, the more potential patients. There's still considerably high risk in adding sites, depending on the type of sites. For instance, we could consider sites out of the U.S. However, populations are very different, and in Euphrates itself, we found different mortality rates between Canadian sites and U.S. sites. On the increasing site performance bucket at the top, We have covered off many of these, but we're doing more of it. On the site training and motivation, we're significantly increasing dedicated resources and running more programs as John will detail further in this presentation. The last bucket, loosening enrollment criteria is very high risk. On the risk curve continuum, it is high risk for little, if any, reward. We have not adopted any of these approaches, and I will quickly run through our analysis on this. And John, feel free to weigh in at any point on this as well. But first, any loosening of enrollment criteria is not likely to receive the FDA's blessing. We worked hard with the FDA to develop criteria for tigris, and any loosening of criteria negatively impacts any comparability with Euphrates data and tigris data. But second, and more importantly, Loosening criteria is in the playbook on how to impair a trial. Broadening out results equals watering down results. Loosening criteria is where trials go to fail. John, anything to add before I pass on the presentation to you?

No, I would just point out that the way you characterize the effectiveness of these steps, which is in that column marked effectiveness, is not a guess on our part. This comes from actual screening data where we can see how patients are screened out. So we could see what, if any effect, eliminating any of those exclusions, even if we could get FDA buy-in to do so, what effect it would have. And you can see that for many of these, they're really quite small.

Great. So, John, why don't you take us through the next couple sections of the presentation where you'll talk about, in detail, trial sites and increasing site performance.

Okay, sure. Thanks, Chris. So, if we go to slide 11, the point of this slide is to really talk about, in some more detail, just how we consider clinical sites for inclusion into tigris. So not just any site is not just any hospital is appropriate clinical trial site only a fraction of the clinical sites only fraction of the hospitals that practice. in the United States do clinical research. And of those, there's only a small fraction that actually do ICU research. So we already started a relatively small number of sites. Furthermore, we really need sites that have experience in sepsis trials. If you look at virtually all the sepsis trials that have been published in the last decade, you'll see the same sites again and again. And that's because there's a relatively small number of clinical trial sites that are sort of experienced with this kind of research. They tend to have board-certified intensivists, 24-7 coverage. They tend to have a very large number of sepsis patients that they've identified per month. We set a criterion of about 50 patients per month. If you get below that, again, this is self-reported by the site, you tend not to be a very robust group. enrollers. So that's how we think about the center. How we think about the site personnel, we begin with the principal investigator. We allow principal investigators that are either intensivists or nephrologist, and then co-investigators that are intensivists or nephrologists alternating, depending on what the principal investigator is. It really requires good cooperation between intensive care and nephrology to make this trial work. It's also helpful, although not required, if there's a supportive lab director and an infectious disease specialist. We then turn to clinical research coordinators. We lose a lot of potential sites because currently in the post COVID world, a lot of clinical research enterprises do not provide seven day support for the clinical trial. Obviously, if we enroll a patient on a Friday, They're going to be run on the therapy on Saturday, and clinical samples need to be collected on Sunday. So it's a 24, it's a seven day a week. It's not 24 hours a day necessarily, but it's seven days a week clinical trial support. We don't expect sites to screen every day, although some sites do screen on the weekend or at least on Saturdays, but we expect them to screen five days a week. That's the only way to really achieve adequate enrollment. Screening has to be permissible in the emergency department, the ICU, or the hospital wards. Otherwise, you miss too many patients. And then finally, they have to be able to run the clinical test. They have to be able to run EAA. Now, that's not a complicated test, but some sites stumble there because they don't have adequate personnel to run the clinical test that's dedicated to clinical research. Then we have nurses that actually deliver the therapy that are different from the clinical research coordinators. These are nurses, typically either ICU nurses or dialysis nurses, and this support has to be 24-7. And it really has to be 24-7 because a patient might get enrolled late in the afternoon. By the time all of the preparatory steps are taken, it may be late in the evening before the treatment is actually provided. Furthermore, if nursing services for dialysis are provided by an external contract agency, which is now fairly common in the United States and has become more common over the last several years, We obviously have to have buy-in and agreement from the dialysis service provider. So these basically are the criteria. And if you turn to the next slide, slide 12, you'll see why a lot of sites don't really pass muster on one or more of these criteria. So we've actually engaged more than 100 sites in trying to identify sites for this trial. You can see that the source of those sites come first and foremost from the prior Euphrates trial in the United States. Those sites in the Euphrates trial that were in the United States, these are clearly the best sites because they have experience with the investigational product, they have a proven track record, and they form our prior data for purposes of the Bayesian analysis. We've quickly gone through those sites, and that's where a bulk of our current sites come from. We also consider 44 additional sites. Most of these sites have come from sites that I've worked with previously in sepsis trials that I've been involved in over the last quarter of a century. Some have come from other sources, including referrals from existing sites. And you can see that then that gets us to this 95 site consideration number and has allowed us to identify a 25 potential sites for the trial as it stands today and will stand in the coming months. If you go to slide 13, you can see this process laid out over time. We began Tigris back in the fourth quarter of 2019. You may recall that COVID began just a few weeks later. And so the trial ran for quite some time amidst multiple starts, stops, because of COVID. When I joined the company in the first quarter of 2021, one of the first things I did was to revamp our sites by adding additional sites, by terminating sites that were not performing, including Stanford and Detroit. And I will say, just in terms of that termination, those were dedicated PIs, dedicated site personnel, and experienced site personnel. And even then, they just couldn't perform. They just couldn't enroll patients. And so we terminated those sites. We added Michigan. We added Colorado. We added Arkansas, Louisiana. In just the last few months, we've added Cleveland, West Virginia, MUSC, and UCSF. We're in the process of essentially finalizing contracts or have finalized contracts with an additional four sites and then five more sites are in the process of getting their paperwork finalized for our complete 25 site complement, which we expect to be active in September of this year. We'll continue looking at sites even after that because the natural history of this business is that you have to replace sites from time to time. Principal investigators don't necessarily stay in one place. Hospitals undergo mergers and acquisitions, and so things change. And so we have to have a robust bench of sites that are available. In trials that I run, I like to have four or five sites that are sort of on the bench that we're evaluating. So we'll continue to evaluate sites going forward. And if we have to increase sites further, we will have a pool in which to expand into. But this gives us our anticipated number of sites that will allow us to complete enrollment in the timeline that we'll show you in a moment. If we go to the next slide, or rather slide 15, we can also talk about site training and motivation. And I have to say at the outset that the sites really are very, very motivated. As I said, I've been conducting clinical research in sepsis for more than a quarter of a century, and I can tell you that the sites that we have are amongst the best sites that are out there. However, it's not enough to simply want to enroll patients in a clinical trial. It really has to be the most important thing as a site investigator or as a site clinical research coordinator. It has to be the most important thing that you do that day. You have to get up in the morning and say, the very first thing I'm going to do is find a patient to enroll in this trial. And when I've exhausted all of the opportunities to enroll a patient in this trial, I'm gonna look again and see if there's any chance that I missed a patient that can be suitable for this trial. And I'll do all of that before I go on and do anything else that I have to do in my busy day. The way to achieve this has always been to have a lot of high touch. to have your technical team, your field team visit sites so often that they say, look, look, I'm happy to see you, but you know, you were just here last week. They really have to be omnipresent at the sites. And this also includes the CRAs, some of which will be coming from the new CRO that we'll talk about for particularly for the new sites. And then finally, I have an important role to play. I visit the sites regularly. I give lectures at the site. I have a, first name basis communication with all of the site PIs. Many of them are people that I've known for many years. We write papers together. We have an academic relationship. Importantly, I've kept my academic credential at the University of Pittsburgh on a leave of absence in part to maintain that academic relationship with these academic physicians at the individual sites because it's important that they feel that connection. But even though these are the steps that we take to achieve high enrollment in clinical trials, it's not been enough. We've been doing all of these things all along, and you can see that our enrollment rate is not where it needs to be. So we have to take some extraordinary additional measures. Now, I'll say at the outset, I don't think there's any way to motivate our principal investigators any further. I think they're as invested as they can be. I think you could argue that some of our co-investigators may benefit from some additional resources and information. But I think our investigators are very highly educated and motivated. They're very informed. And I think our CRCs are very highly motivated. I think our CRCs are also very educated and informed. But again, what makes them want to do this more than anything else? What makes them want to do work for this trial more than anything else? We can't pay them anymore. We're already paying them top rates. There's no way to incentivize them with money. That's not permissible. So what really gets them up in the morning? What gets them to do this work? It's really clinical success. The fact that they can actually enroll a patient in a clinical trial and see that it's actually benefited a patient, that's what gets them up in the morning. The reason that these people, and I've known them for 40 years really since I was in medical school, these people are motivated by trying to do something that benefits patients. And so they want to not just feel that this is going through the motions because it's their job. They want to feel that this is stopping at an accident scene. This is helping out when people are in desperate shape for something. How do we achieve that? Well, first and foremost is helping the PIs, the principal investigators at the sites, motivate their own teams. And we can continue to provide resources to them in order to achieve that. Investigator meetings, as we'll talk about in a moment, are extremely helpful in this way. And this particular one, we have some patient speaking, which will provide additional clarification of just how important this work is. In addition, there's a lot of academic detailing in the form of publications and speaking at conferences, which I spearhead. And then extraordinarily, we've taken a step of moving to the lay press, and we'll talk about that as well. If we go to the next slide, we'll see the very first one of these new steps, which is to transition our CRO. And one of the things that you always have to consider in a clinical trial, if it's running long, if it's not achieving the success that you would like. And I will say that Tigris is achieving enormous success as we'll talk about in a minute in terms of outcome, but the enrollment rate continues to be slow. So one of the ways to address that is to look at your CRO and decide whether it has sufficient resources in order to support the clinical sites. This is a major undertaking. You don't undertake it lightly. But I think extraordinary circumstances really require extraordinary moves. And so we have changed our CRO. We're in the process of transitioning to a new CRO. that has very strong clinical support, that has very strong biostats, which is important to us when we get to the end, and strong regulatory support as well, which will be very important. This CRO will allow us to manage the additional sites as well as to help facilitate management of existing sites. They'll be bringing additional clinical field resources into the operation. And they'll provide a clinical review and evaluation of recruitment and enrollment at each site and report back on that information so that we can exercise necessary steps to achieve the enrollment rates that are needed. This transition timing has already started. We had a kickoff meeting just a few days ago. And we expect to be complete in that transition by the end of May. If you go to the next slide, slide 17, you can see the full complement of clinical resources, including the new CRO, that will now be available. So there are several things that are important to emphasize on this slide. First and foremost, I want to make it very clear that the reason that I joined this organization was to complete this trial. It is important to me personally and professionally, that this trial succeed. So important, in fact, that I left a good job at the University of Pittsburgh, where I ran a clinical research operation for many years. I don't take that transition lightly. And in fact, it's really the first and only professional transition I've ever made in my entire professional life since completing my residency and fellowship. I will be seeing this trial to completion and we will be getting this trial over the line and will succeed in getting clinical approval from the FDA for this product. That's the reason that I came here and I take it very seriously. It's very much the culmination of a life's work in sepsis and extracorporeal blood purification. And I have to also say that of the more than a quarter of a century of clinical trials that I have run and participated in, I actually have more support in this trial to achieve these goals than I've ever had before. I have both quantity and quality of support from various individuals in order to achieve success in this trial. And I have to say that I am very confident in both my clinical team and I'm very confident in management and the board in order to secure the necessary funds to complete this trial and in helping in the various ways that are necessary to achieve success. And then finally what's shown on this slide is the additional resources that have become available because of the new CRO and because of the Idealco transaction. So I just want to emphasize that we now have the resources that are necessary to complete this clinical trial in a positive way. If we move to the next slide, there's more detail about the investigator meeting. Now investigator meetings are very, very integral to clinical trials. We conduct not only an investigator meeting at the launch of a clinical trial, but we typically do it, say, midway through the trial, and we often do it toward the end of the trial to push for completion. This is not the first investigator meeting that we've had, but it's only the second in-person investigator meeting that we've had because of the disruptions related to COVID. The last meeting that we had was a virtual meeting. And although that meeting was successful in increasing enrollment, primarily by affecting those changes in attention and motivation that we spoke to previously, an in-person meeting is important. And this one will be extremely focused on enrollment. We have a keynote speaker who's actually a sepsis survivor, a patient who can speak very eloquently about just how important it is to conduct clinical trials in this site. This is the kind of passion that's necessary for the type of motivation of the individuals that we spoke about. We'll also have introduction of new sites. We'll have an introduction of the new CRO. We'll conduct patient consent workshops and various breakout Slide 19 details that academic detailing that we talked about, the sort of providing investigators with education, with information that allows them to disseminate the kind of information to their colleagues and to the clinical research coordinators. This is disseminated through publications that I'll show you on the next slide. But also through lectures and presentations at international and national meetings. And you can see a list of many of them there. The next slide, slide 20, details quite a number of publications that have been published in the last year, as well as some of the trials, some of the publications that are slated to be coming out in 2023. The next slide takes us to something that I never dreamed we would ever have to do, but I think it's absolutely essential. So the producer of this program, this daytime television program, contacted us several months ago because they heard about both the problem, which is endotoxemic septic shock, but they also heard of spectral, and they wanted to do a segment in their program on this. They do many medical segments. They're actually quite high production value. You can check them out on their website. And we were initially, I think, a little bit... disinterested in having this. We thought, well, that's fine, but what value does it really have? to us until we complete the clinical trial. And then we began to think about it more and more, and we began to talk to the various stakeholders and the various sites that are working with us. And we really realized that, and you can do this yourself, you can go to Google and you can type in polymyxin B hemoabsorption, and you'll see that there's quite a lot of material there, but it's not written at a kind of a layperson level. if you're really just trying to find out information about this because, you know, you're a nurse in the dialysis unit and you've been asked to pitch in and help with a treatment tonight and you've got dinner plans, you know, one of the things you might do before you decide to accept that challenge is just going to say, what is this all about? And you don't want to have just a list of publications with P values. You want something that is sort of a quick, little snapshot that's in lay terms that you can understand. And, you know, if you're someone trying to understand this, this is the kind of thing that's available. And this is because the world has changed. We're now in a position where we really weren't even a decade ago in the sense that the kind of information that people expect to have at their fingertips the information they expect to be able to pull up on their phone needs to be information that's been prepared for them. And so we're moving forward with this. This program will have not only a TV spot, but it will have a targeted social media and digital activation in conjunction with essentially numerous broadcasts impressions. It will result in a digital version of the segment that we'll have the full licensing rights to and can use for our purposes. This streams continuously online and so anyone going to Google and trying to find information about us or about PMX will have this information at their fingertips. So again, it's an extraordinary step, but we feel that the current situation calls for it. If you go to the next slide, I just want to talk about the impact of all these things on the enrollment timeline. I've done an analysis of the last 12 months. And the reason we looked at the last 12 months is this was really the 12 months where we really did not have any real COVID factor in terms of the patients themselves. There's still a legacy. of effect of COVID on the sites, the short staffing that continues to be a result of COVID. But COVID really hasn't been a factor in our ability to enroll patients in terms of patients having COVID in our ICUs really for the last 12 months. And we've enrolled basically two patients a month in the trial. where on average we had effectively about 11 active sites, 11, 12 active sites over that period of time. Got up to 14 sites by the end of this year, but three of those sites were new. So effectively, you can calculate that we've basically had enrollment, as Chris said, of 0.182 patients per month per site. Now, although that rate's lower than it needs to be, and that's why we're here, it also is important to recognize that that's really not an unusual rate for these kinds of trials. And indeed, the Euphrates trial, the closest trial that's out there, actually had a enrollment rate that was lower despite having fewer exclusion criteria. With our site projected onboarding that I've showed you of getting to 25 sites by September of this year and then having a full complement of 25 sites thereafter, it effectively means for the next 12 months we'll have a fraction of those 25 enrolling. So it essentially means that it'll be 21.1 sites is what it works out to that will contribute for the next 12 months and then after that a full 25 sites. You can see that if we were to increase enrollment by a small margin, going up from 0.182 to say 0.22, even 0.25, which I think are realistic. I think it's unrealistic to say that we can get above 0.25. But you can see at that range, going from 1.82 to 0.25, that the trial will not be finished. enrolling before September of 2024. That's that bottom row. And worst case scenario, which I think is reasonable to assume that all of our efforts have no effect and we stay at 0.182, will be finished in March of 2025. So I think the range of uncertainty between these two extremes really defines what we expect

terms of how long it will take to finish the trial given these assumptions so Chris anything to want to add to that no John that was great I think you know once again we've been able to reground and rebase our assumptions for enrollment rates though you know certainly we we came in with maybe ambitious, if you will, enrollment rates coming off of Euphrates, but I think we had good reason to believe that we could achieve those at that time. But as we have seen, the world in clinical trials has changed, and we've had to adjust, and this is what I would say is the new reality. Great. So John, I'll just pick it up from here. Just turning to slide 23, we look at the interim release of data. We get the question, it's an open-label trial. Can't you release the interim mortality data? So the answer to that question is it's not that simple. Our intention is that trial results will be analyzed at the end of the trial when all data are cleaned and verified. We do not have an interim analysis in our protocol. As such, There are negative implications should we release on an unscheduled interim basis, including statistical penalties that could further require lengthening our trial or reduces the power of our trial, both negatives and risks. That being said, as of 53 patients, our crude mortality data are exceeding expectations. As a reference, the Euphrates subset benchmark that we targeted for tigris is 10% absolute mortality benefit. When we characterize it as exceeding, that doesn't mean by just one or two percentage points. I would characterize that magnitude as being more in line with just meeting the benchmark. So in the absence of an interim data release, are there any comparable study results? Well, yes, there are. The first is UFIS II study in Italy. We anticipate UFIS II study results to be published in Q2 of this year. and our understanding is that it is in peer review stage. The other is an Eastern European observational study, I believe in Poland, where EAA was utilized, and it shows remarkably similar and extremely consistent survival curves to tigress. John, I don't know if you have any input or want to chime in about the chart on the right-hand side.

No, this was common. The references at the bottom there, if anyone wants to look at the full publication, this was an observational study. But it's remarkably in line with what we're seeing so far in terms of accrued analysis. Again, as Chris pointed out, we're not going to do any actual analysis of data. That comes with statistical penalties. We won't do that until the end of the trial. But we do look at where we are in the study and the results that we're seeing are very much in line with these historical references. Another point that I want to make is that we often do, just in terms of trial management, we do look at what's called the composite mortality rate. If the composite mortality rate is too low, then you know you're not enrolling an adequate severity of illness of patients. And this is often the thing that trips studies up. If you look, for example, at the recent AM Pharma revival study that was just announced a few days ago, You can see that their composite mortality, meaning the mortality in both the control group and the treatment group, came in at 28-day mortality at less than 30%. And we've always been targeting a mortality rate greater than 40% in the TIGRIS trial, and I can confirm that we are achieving that.

Great. Thanks, Sean. So, just turning to slide 24, could we consider an early stop to TIGRIS, or put another way, The results are so good. There's no solution for such a malignant disease. Why can't you go for early stoppage and accelerated FDA approval? So first, our trial has no mechanism for an early stoppage, and the FDA would need to agree to a change. But more important is that there are a number of risks to stopping early, the most important being the credibility of the results. The trial is already viewed as quite small at 150 patients. If the results questioned FDA approval would be in jeopardy as will market acceptance and willingness to pay, even if approval is granted. There's a graveyard full of early stoppage stories, and I think it's worthwhile to briefly talk about a couple, the first being Eli Lilly's Zygris sepsis drug. It received FDA approval after an early stoppage at its second interim analysis. The FDA approved Zygris, but one, approved a strict indication for use, and two, required three large, and expensive post-market trials. The clinical community was skeptical to the point of writing articles in the JAMA on how flawed the trial was. The product was ultimately pulled from the market in 2011. Zygris might have actually been a good product, but never reached close to its potential. A more recent example is Biogen's Agihelm. It's an Alzheimer's drug. In 2021, it received FDA accelerated approval. Once again, the scientific community was skeptical. CMS limited its coverage, leading to commercial failure. And Adjahelm was completely pulled off the market in approximately 12 months after approval. So before I leave this slide, John, is there any insight or perspective you want to add to this?

No, I think you said it well, Chris. There's a general, and it doesn't take much effort to find multiple editorials written about early stoppage of trials. There's just a general sense among the scientific community that, If you say you're going to run a trial of 150 patients, if you don't make it, it's akin to cheating. It's just not believed to be as rigorous as it could be. And the FDA has a similar view. So it's really something that you have to take very, very seriously and avoid really at all costs.

Great. Thanks, John. Moving to slide 25. We've shown this many times before, but this once again points to the robust financial returns and shareholder value potential of our platform. We're operating in an untapped $2 billion annual market with no competitors. We're well positioned to unlock significant shareholder value and I'll quickly reiterate what I've said in the past. We have the best commercial partner in Baxter. We said it day one and we continue to say it today. They've shown themselves to be committed and collaborative partners and continue to allocate and invest commercialization resources from marketing from regulatory, clinical, reimbursement, and not to mention their approximate 50% market share in ICU CRRT devices, which we intend to run the PMX therapy on. From a spectral net economic benefit perspective, our platform has incredible shareholder value potential. In the table on the right, we continue to show market penetration rates and what this could mean to spectral from an EBITDA perspective. As you can see, it's robust. anywhere from tens of millions to hundreds of millions U.S. If I look at how this might translate into share price potential, I'll just lay down some illustrative math here. Comparable medical device companies such as Jafron traded an EBITDA multiple of, call it around 20 times. For the purposes of our math, I'll use 10 times. I'll multiply that across various net EBITDA scenarios and then divide by call it 280 million shares outstanding today. that results in some pretty attractive share prices. That being said, if you add 50 million or even 100 million shares in dilution, and I'm not saying we're going to do that, but I want to illustrate the extreme. You still end up with almost equally attractive illustrative share price ranges. So for a shareholder that invested today or yesterday or even longer than that, the potential total shareholder returns could be spectacular. Moving on to slide 26, we look at what the U.S. addressable market could be for PMX. A fair question would be, management speaks about 140,000 patient addressable market, yet you've only enrolled 53 patients. Is this addressable market really as big as you say it is? So as we know, the tigress inclusion criteria is strict. It institutes constraints on PMX utilization in a clinical trial setting. These same constraints likely fall away in a clinical practice setting in a post-approval setting. So when we look at our screening data, a number of exclusion criteria would fall away in a practical sense, resulting in something along the lines of 16 patients out of 100 that could be treated or 1.2 patients per site per month transposed across the U.S. ICU universe gets us approximately 300,000 to 400,000 patients that may be appropriate for PMX therapy. I'll let John walk you through the chart on the right-hand side of the slide, given his practical ICU clinical experience and how clinicians would assess suitability. John?

Yeah, thanks, Chris. And this really does come out of, you know, how I would essentially switch hats, right? So as I move from being a clinical trialist to actually at the bedside taking care of patients, which is something I still do, this is sort of how I would view the appropriateness for potential appropriateness for a product that's approved and is available to treat a patient. So, you know, the first few bars don't really change, right? I mean, septic shock and again, the type of septic shock as defined by the dose, I'm not going to change any of that. I'm only going to treat patients who have that amount of endotoxemic septic shock and that amount of severity. But this vasopressor window largely goes completely away, right? Because often that comes from the fact that the patient is at another center and they've been transferred over or that the clinical research team didn't find the patient because they came in late on a Sunday afternoon. All that stuff disappears when you're actually providing the therapy for clinical use as opposed to in clinical trials. So I don't discount that. enrollment at all for the vasopressor window. I do for organ failure because the organ failures will likely be in some form or another part of the label, and I'm not talking here about using the product off-label. In fact, I'm talking about staying very much on-label, and still we're going to have patients that are excluded because of organ failures. However, if There are some exclusion criteria that are entirely a part of the clinical trial methodology that won't actually be in the label in all likelihood. And even if they were, clinicians are not going to exclude patients from getting life-sustaining therapy for things like HIV status, right? The patient may have a malignancy, but if the physician says, without sepsis, I think that you would survive for another three or four months. I'm not going to deny you this therapy because you have a malignancy, even though it's something we exclude in a clinical trial. And then informed consent obviously goes away completely. And then this non-survivable aspect is important because Again, it's a different mindset. When you're a trialist, you don't want to enroll a patient who's going to die in front of you. You don't want to enroll that patient or you have a lot of hesitation to enroll that patient in a clinical trial. However, if this is the only therapy that's available to a patient who's dying in front of you, you won't hesitate to use it. EAA, we're still constrained, and so that bar still shrinks by the same proportion. And then some of the logistics, I kept some of them in because, you know, there are always going to be some logistical factors, but there's going to be very few times when something like, oh, gosh, we don't have a nurse to run this, that really doesn't happen when the therapy is standard of care. It happens in clinical trials because clinical research is thought to be something extra, not part of the clinical mission. So this is how we landed on this number of 16 as opposed to 0.5 to 1. And you can see there's obviously quite a difference between who might receive the therapy in clinical practice, between who's eligible to be enrolled in the trial.

Great. Thanks, John. Moving on to slide 27, we look at spectral share price performance. Spectral is certainly on better footing and better position to unlock shareholder value than probably any time in its history. So where we sit with today's share price is extremely frustrating. On a relative basis, whether you benchmark against peers or the broader market, our share price has held up well. That being said, we believe that share price appreciation in Spectral is tied to increasing patient enrollment, which we've discussed and focused on today. So how does this impact funding of this business going forward? What I can say is that we are a development stage company and we're always considering funding alternatives. It's a constant and top of mind for this company. We have funding alternatives available to Spectral, even in the worst of markets. Take last year's capital raise. we were able to find significant lead orders with patient capital to drive that financing on very attractive terms. Any comparable deals getting done last year came with significant, if not crushing discounts and warrant coverage. Once again, with any future capital raises, we will assess which alternatives can get us through to clinical completion at the lowest cost of capital. Moving on to slide 28. An overview of the IDALCO joint venture transaction. We assessed a number of alternatives and entering into the IDALCO transaction was the best avenue for at a minimum protecting spectral shareholder value and maintaining the potential for upside appreciation. The dialysis device business is a highly capital intensive business. There are no outliers in this business. Look at Next Stage, look at Outset. They've burned through hundreds of millions of dollars and still weren't or aren't profitable. If you want to talk about potential dilution, the dialysis device business has the ability to be a cap table killer. In entering into the transaction, we're able to eliminate capital commitments, reduce operating expenses, and, as we've discussed today, focus our resources and capital 100% on executing the TIGERS trial. Moving on to slide 29, we've laid out Spectral's upcoming catalysts. The addition of new sites, it's well underway as discussed. TIGRIS enrollment and acceleration from where we are today, that's pretty much 100% of what we discussed today, but more importantly is the key to unlocking some very high value add milestones. The first being TIGRIS quote unquote interim patient enrollment of 90 patients. Why is this such an important catalyst? because it's tied to the Baxter milestone payment number two. This is where Baxter will get to review TIGRIS raw data and have the option to exercise its right to maintain exclusive distribution rights and pay the second milestone payment to Spectral. This will be continued validation that TIGRIS is on the right track for a successful FDA outcome. Obviously, full enrollment should act as another huge catalyst. As a reminder, TIGRIS is an open label trial. We wouldn't run this to full enrollment if potential FDA approval was futile. Post-full enrollment, we would release TIGRIS top-line results. This would be approximately 60 days or so post-database log. At this point, the general market will get a specific view of absolute mortality benefits as well as relative mortality benefits of TIGRIS. And finally, there is what we have been working towards all these years, PMX FDA approval. I don't need to emphasize how big this catalyst would be, but just as important is it's tied to a final milestone payment by Baxter. So before we get to the Q&A session, I would just like to wrap up the presentation portion with some concluding remarks. Current TIGRIS results continue to exceed expectations. We are on the right track. We've built a strong foundation for success. We have de-risked the regulatory side with the design of the TIGRIS trial, and we have de-risked commercialization with our Baxter partnership. Today, we have outlined significant steps to get TIGRIS enrollment accelerated. We have an actionable line of sight on onboarding 25 sites. We have a full complement of focused and dedicated clinical resources to execute this trial. And we have the motivation and awareness campaigns to continue to improve enrollment productivity. And most importantly, we are positioned to unlock significant shareholder value. PMX economics are robust. With an estimated $2 billion market, and targeting the most malignant form of septic shock with no other therapeutic solution. Thank you very much, and we can now open up the call for your questions.

Operator, we'll take questions now.

Okay, great. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone's iPad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star 2.

One moment please while we poll for questions. Thank you.

Our first question is from Kevin Vinstra, a private investor. Please proceed with your question.

Thank you today for the informed update. It's been really good. Just a few questions for you. The first question is, how much additional money do you think needs to be raised before we hit the 150 patient enrollment? Second question is, it was really nice to see the comparison of enrollment rates with Tigris versus Euphrates, and you show how the Tigris enrollment rate is in line, if not better than the Euphrates. But I'm still questioning why you thought at the start of Tigris that you'd be able to get it done so fast, given the history from the Euphrates. And my third question is, I think this is more for Dr. Kellum for sure. is around, I know you started after Euphrates was finished already, and the post hoc analysis, of course, was very good. What is your personal thoughts in terms of why the end result on the Euphrates didn't hit the mark? I'd just like to get your personal opinion on that.

So three separate questions there. Thank you.

Hey, Kevin. This is Blair. Just with regards to additional funding required, we're looking at basically $17 million to bring this trial to completion. That contemplates direct costs of tigris, costing $7 million to complete, and the difference related to our operating costs effectively month to month.

Kevin, I believe that gets us to FDA approval. So it's not just completing the trial. It's call it the six, seven months after last patient enrollment. to get to FDA approval.

Okay, thank you. And I know in previous PowerPoint decks there was some discussion of potentially listing on the NASDAQ. Is that still something in play? Or given current market conditions, is that something that's maybe not as likely to happen? Can you comment on that?

Yeah, Kevin, I think we've made our position, I think, pretty clear in the past that whether it's NASDAQ or NYSE or, you know, obviously U.S. Senior Exchange. I think it is appropriate. It's appropriate at the right time, though. And I think as we accelerate enrollment and we see a regular cadence of strong enrollment, that could give us the tailwind to make that move. I think if we are a stagnant story, that – would be a mistake. It would be a waste of energy and a waste of money at that point in time. But there is the acknowledgement that, listen, our end markets is the U.S. market. That is our biggest market. And there are exceptional and deep capital pools geared towards stories like ours. We just need some momentum, I think, before getting there.

Okay, that's good. Thank you.

And sorry, you had a lot of questions there. So in terms of our original assumption on sort of one patient per month per site going into Tigris, there really is, there was grounds for that. So when I talked about the 0.136, that was the average over the length of the trial. But if you actually look at the enrollment curve, It is very low at first, similar, and then jacks up, call it the last 20% of the trial. And when you looked at or when we looked at our top performing sites from Euphrates and their enrollment rates at that time, and I think this now goes back to 2016, they were robust. And so transposing that, I don't think was a flawed assumption. I think there was definitely basis for that at that time. Some of the other things that we did talk about, certainly, obviously, they were our best recruiting sites. And so at that point in time, that's the assumption we went in with. I think the last 12 months, as Dr. Callum has explained, we've had the first point in the trial where we've had consecutive 12-month runway of basically COVID not impairing trial enrollment. And so this has given us sort of at least the confidence for a base here to reground the assumptions.

That's good. And then my last question was...

Sorry, maybe just maybe just to jump in on that. I because I think your last question is for me to Kevin, but I think that it's also important to recognize that. And again, not none of us, none of the three of us were around when the original assumptions for the design of Tigris were were made, but In 2020 hindsight, I think it's worth recognizing that when this trial was launched in 2019 pre-COVID, you know, some assumptions that may have made sense back then, the world has changed and the clinical research enterprise in the ICU has changed. I can tell you that running trials in 2018, 2019, that it was not the buyer's market of the clinical trials now where sites really can pick and choose what trials they want to participate in. They can pick and choose how they exercise, weekend enrollments, and all kinds of things like that. So I think that's a factor. I think it's also worth reflecting on the fact that we knew straight away that by removing 17% of eligible patients from Euphrates, meaning those patients with an EAA above 0.9, we really had no good way to estimate just how that proportion would work out at different sites because it's small enough. that, you know, we pick a site like the site that I know very well, University of Pittsburgh Medical Center, you know, will they have more patients in the above point nine? Will they have less? Will those patients come in during the week or during the weekend? So there's a lot of uncertainty. And so I think that accounts for some of that. But as Chris said, I think, you know, the last 12 months really gives us the best snapshot of information that allows us to project out into the future. And in terms of your question around why did Euphrates fail, I think that it's worth, and just for full disclosure, you may recall I was on the Data Safety and Monitoring Board for that trial. So I did see the data as it was coming in. I know the data quite well. And it's important, I think, to recognize that we made a mid-course correction. The company made a mid-course correction on the basis of DSMB recommendations halfway through the trial when it was recognized. And I will also point out that what was recognized was that patients with a low organ failure burden didn't benefit from PMX. The benefit of what there was in benefit came for the patients in a high organ failure burden. This has actually been borne out now in studies in Japan where people have actually looked at SOFA scores relative to benefit and have found that low SOFA score patients don't benefit from PMX. So I think that's part of it, right? Had we started the trial with just focusing on patients with a high organ failure burden, I suspect the trial would have taken even longer to enroll, and that might have jeopardized his completion, but it might have had a better chance of success. And then obviously, if we would have known about that 0.9 and above, that would have changed everything.

Okay, that's good.

Thank you so much. Thanks, Kevin.

I would like to turn the floor back over to Ali Mahdi for closing comments.

Thank you, Operator. Obviously, we have no further questions in the queue. We hope this call has been valuable in addressing some of your questions and concerns that we've been hearing about. As a reminder, a replay of this call will be available until April 13th. That concludes today's call. I will turn it back over to the operator to close things off.

Thank you for your time today.

This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.