Hello, this is Jonathan Aschoff, senior biotechnology analyst at Roth Capital Partners. I'm here now with James Rolke, the CEO of Revelation Biosciences. James, welcome. How are you? I'm good, Jonathan. Thanks for having me. Let's just step back and tell everybody about Revelation. Yeah, sure. Revelation's a clinical-stage, actually now I can say a later clinical-stage biotech pharmaceutical company. We're developing our lead program called Gemini, which is our proprietary formulation of phosphorylated hexaacyl disaccharide, also known as PHAD, easier for people to say. Our lead program is actually on the use of PHAD to treat acute kidney injury, which is a significant unmet medical need. We have our other value-adding program is Gemini for the treatment of chronic kidney disease, for which we're developing an oral version of Gemini. Can you maybe dig a little deeper and tell us how Gemini works? Absolutely. I'll have to bear with me with some biology for a minute, but I'll make it as simple as possible. I am, after all, a chemist, I'll make it very simple. Basically, Gemini, the active ingredient I just mentioned is PHAD is actually a small piece of lipopolysaccharide, also known as endotoxin, you're like, "Okay, what the heck is that?" Bacteria and cells are comprised of lipopolysaccharide. It's the lipopolysaccharide in a cell wall that interacts, and in particular in this case, it interacts with a receptor called Toll-like receptor 4, which is found on a number of immune cell surfaces. When lipopolysaccharide interacts with Toll-like receptor 4, it activates a pathway called the MyD88 pathway, which leads to the upregulation of a number of inflammatory cytokines. In fact, it's why when you get a bacterial infection that you get a fever. It's because you're stimulating Toll-like receptor 4 via this endotoxin. What PHAD is PHAD is a really small piece of that endotoxin. When it interacts with Toll-like receptor 4, it activates the MyD88 pathway, but only to a very small degree. It predominantly activates what's called the TRIF pathway, when you activate the TRIF pathway, you actually get upregulation of a number of inflammation resolving cytokines. Cytokines is a fancy term for the molecules that cells put out that tell other cells how to behave around it. It's interesting, the reason why we believe that is if you think of it from an evolutionary point of view, when you first get a bacterial infection and the cell walls of bacterial are intact, it activates the inflammatory pathway so you can fight the infection. As you start to overcome your infection and the bacteria start to break down, you're making small pieces of those walls because the bacteria are dying and breaking down. It's the same receptor, the Toll-like receptor 4, that recognizes these smaller molecules, and it's telling the body and the other cells in the body, "All right, we're overcoming the infection. We need to turn down inflammation." Why is all that important? Because I'm talking about infection in inflammation. It's because it's that same pathway that you can use, that activation of the TRIF pathway. You upregulate those cytokines that tell the body, "Okay, cool it. It's time to start settling down." You can apply that to any type of an inflammatory disease. That is basically the genesis of how Gemini works. That's great, but why don't you tell us what you've shown in humans thus far to support that? Great. Yeah, that's a great question, I'll answer that twofold because it's not only human data, it's also preclinical data. Let's start with the human data. We just recently ran a phase I-B study last year in 2025 in chronic kidney disease patients that were either stage 3 or stage 4 chronic kidney disease. Just to put it into perspective, stage 4 chronic kidney disease patients are only one step removed, essentially, from going on to dialysis, so they have limited kidney function. The hypothesis that we wanted to test in that study is, first and foremost, is do those patients have a high background of inflammation? The way we looked for that was is we collected prior to dosing with either placebo or with our drug, Gemini, we isolated blood from the patients, a few milliliters of blood, then further isolated their peripheral blood mononuclear cells. That's a fancy way of saying immune cells, white blood cells in particular. Then we cultured those ex vivo in a lab dish, we looked for the upregulation or the production of inflammatory cytokines. What we showed in chronic kidney disease patients is that a vast majority, greater than 80% of chronic kidney disease patients have upregulated strong backgrounds of inflammatory cytokines. They're constitutively making inflammatory cytokines versus a healthy volunteer. If you collect those same PBMCs in a healthy individual, which we did, and you evaluate them, they are not producing inflammatory cytokines. What happens when we administer Gemini versus placebo? Well, it's very compelling data. What we observed is that when you treat people, so we're injecting the material into people, and then you take blood at various time points after they have been administered Gemini. You look at those peripheral blood mononuclear cells, what we showed is that the placebo, there's no change. The cells continue to produce large amounts of inflammatory cytokines like IL-1 beta and IL-6. When you have the Gemini on board in a very durable response, you basically normalize the cells. You take their background inflammation back down to what is observed with normal healthy cells. That response in some patients actually was durable out for seven days. Again, this is following a single dose of Gemini. That's a very important point. It's a very powerful drug in this particular instance. The other thing that we observed, which is also well documented in the literature, by the way, is when you have this constitutively high background of inflammation, your cells become immunoparalyzed to other stimuli, meaning they don't respond to a second stimulation. For example, if you're sick in a hospital and you're in there because you have pancreatitis or whatever, then you develop an infection, your body can't really respond to it because it's immunoparalyzed. You're just pumping out a lot of nonsensical inflammatory cytokines. What we observed also in this clinical data is not only do we suppress and normalize their inflammatory background, but we also restored their responsiveness comparable to a healthy volunteer's cells to two different stimuli, either LPS or HMGB1. That's very compelling data. What that data shows is we're not an immunosuppressant. We're in fact doing exactly what we had hypothesized that Gemini would do, which is we are actually rebalancing the inflammatory response. That's the human data in a diseased patient. Just to touch on a little bit about the preclinical data because it ties everything together, bear with me on this one point, is that we did conduct a model, an acute kidney injury model, where we ligated an animal's kidney and left one kidney healthy, but the ligated kidney basically explodes with inflammation. When that happens, it very rapidly scars, just like you would get in an acute kidney injury case and/or in chronic kidney disease. What we showed in that model in a nice dose-dependent manner is that Gemini administration, while the active inflammation was going on, actually significantly reduces the amount of new collagen formation. Also in that same animal model, we showed downregulation of pro-inflammatory cytokines, meaning things that propagate the inflammation, as well as upregulation of those anti-inflammatory inflammation resolving cytokines. Very powerful data. The last little bit of data, I'll tie everything together, is when you look at cytokines in healthy individuals and healthy animals, what we showed is that in the same species that I just described the test to be done in, we see a nice upregulation of anti-inflammatory cytokines upon administration of Gemini. We know in animals that you get the nice panel of protection. In healthy volunteers when you administer Gemini, you get that same type of response with the same type of panel of protective cytokines. How does that all tie together? Well, what we've shown is that in healthy animals, you get protection. In healthy humans, you get protection. In diseased animals, that protection translates into a better outcome. Now most recently in this CKD study, we showed that in diseased patients, that same cytokine panel results in a better outcome vis-a-vis the fact that their constitutively on cells return to normal. Hopefully that helps to answer that. Yeah. As much sense as that makes, you recently met with the FDA. Can you tell us what they had to say about what you presented to them? Yeah, that's a very good question. We met in December of last year on the heels of that very compelling phase I-B data that we were actually very excited about and still are. We went there with a couple of objectives when we met with them. The first question that we asked them, and I'll go in the order of not necessarily importance, but probably the most impactful, is we asked, based on the data that we've generated to date, both clinically and pre-clinically, can we conduct a single adaptive phase II, III study design? Should we be successful in meeting our primary endpoint in that study, would this data be submittable for approval? The answer from FDA was yes. If you run the study, an adaptive phase II, III study, and you meet your primary endpoint, you can submit that data for approval. That's a huge win because now that's why I said it at the beginning, we're now a later stage company. The next study we run is a pivotal registrational study. That's number 1. Number 2 thing we asked was is we said we'd like to get a composite endpoint comprising both death and number of days on dialysis. This is an endpoint that actually has never been given before. People have tried to get it, and we actually were quite successful. FDA agreed to our endpoint, the reason why it's relevant is it's because it's a highly objective endpoint. You're either on dialysis or you're not on dialysis. You're either dead or you're alive, right? There's no touchy-feely scale that you have to fart around with. It's a yes/no answer, you get this composite score. It's a little bit more complicated than that, but nevertheless, the point is that composite score is important. The last thing we asked is can we run the adaptive design as it's written? The beauty of that, I'll spend a little bit of time on this because this is a very important point, is the adaptive design offers us an opportunity to first, in this patient population, we know what the ideal dose is to elicit a response. What we don't know and what FDA actually recommended is we should look at multiple doses, meaning giving more than once. They highly encouraged that. We had already had an idea of doing at least one other dose. They said, "No, go bigger. Do more doses." They think that's a good idea. We're doing four different dosing arms of different dosing regimens versus placebo, and at the end of the phase II portion of the study, which is approximately 185 patients, the safest dose, as determined by a Data and Safety Monitoring Board, will be graduated to go into phase III. The beauty of the adaptive design is a couple of fold. One, all the data that you collected at the dose that moves forward to phase III, plus all the placebo data, all counts towards phase III. The second part of the study is only about another 130 patients to complete. It's roughly around a 300 to 350 patient study. That's number one. The other thing that you get out of an adaptive design that's very important, because it's a huge money saver for the company and it's just showing that we efficiently use our cash, is normally when you run a phase II study, if you stop and you collect all the data and then you start a phase III, the time between phase II and phase III is like a year, and probably like $20 million-$25 million of burn. In an adaptive design study, the time from phase II to phase III is a week, and you actually never stop enrolling patients, because as you may imagine, Jonathan, starting a clinical study and getting patients and clinical sites up and running is not a trivial matter. Very powerful. The last thing I'll say about the adaptive design is the other thing the FDA agreed to is we can have an independent statistician at the end, after the dose has been graduated, do a sample size recalculation so that we know that we'll be able to hit our primary endpoint into phase III. Why is that important? Let's say, for example, the independent statistician concludes we need to enroll 1,000 patients. That means the drug's probably not doing anything, which means we probably wouldn't continue to do the study. If he says, "Oh, you might need to enroll another 30 patients to meet statistical significance," then we'll enroll those. I can tell you from my own personal experience, I've been at companies where we've had the conversation, "Oh, if we'd only enrolled 30 extra patients, we would've reached the significance." In this particular instance, we're going to get to have our cake and eat it, too. That's a little bit about the FDA interaction. Very briefly, just talk about acute kidney injury and what gives you confidence that about the trial. For acute kidney injury, hospitalized patients develop ICU. You develop severe AKI stage III, that basically means you need to go on to dialysis. When you go onto dialysis, the likelihood of you dying goes up every day you're on dialysis, and it's not a linear relation. Every day that you're on, it proportionally goes up in an almost an exponential manner. If you're on dialysis for three days, you're way more likely to die than if you were only on for one, just as an example. The point is dialysis, unfortunately, is the only treatment available, so it's a huge unmet medical need. Just in terms of, sorry, the second half of your question, a little bit about the clinical study itself. As I already described, the phase II portion of it will be five different dosing arms where we look at different dosing regimens of Gemini versus placebo. The total size of the study right now is estimated to be somewhere between 300 and 350. That's for both the phase II and the phase III portions of the study. As far as timing is concerned, we're actually in the process right now of identifying and hiring a top-tier clinical research organization. I can't emphasize how important that is. You want to get in bed with somebody that's going to be able to do the job, and we're predominantly planning on conducting this study all in the U.S. at about 30 to 40 different sites. That's very important. We're manufacturing drug product and placebo to support a randomized controlled placebo-driven study. Lastly, we're in the process of forming a very strong scientific advisory steering committee, KOL board, to help guide us through the process of running the study and help us to develop the best drug possible. Lastly, about the clinical study, our plan is to initiate the study late this year, probably in late Q4 of 2026. Some financials, or some financial parameters here. Describe, with your assumed pricing, if you can estimate what you might charge for it, what your AKI total addressable market would be, and after that talk about the company's financial position and how far its cash carries it and such. Good question. A little bit about the market. Anybody that wants to read the details on this can look at our presentation on our website, because I'm a chemist and I'm not going to butcher numbers. What I can tell you is that the addressable market is much larger than the market that we are predicting in the sense that we're saying we're using a very conservative and we're looking at only the [audio distortion] with that conservative just for AKI alone. Depending on how well a drug works of the sick that it gets used, but again, a very lucrative market. I will touch on also the follow-on program in CKD that we're looking at, because we do believe for chronic kidney disease, based on our clinical data, that we would have an impact there. We are developing a oral version of that also with a conservative market penetration and price point is a $9.2 billion a year market. Lastly, just to wrap up on the marketing stuff, is if the underlying biology is sound, which we believe it is based on all the great data I just described and this clinical study, any inflammatory disease would be potentially addressable, either acute or chronic with Gemini. There may be some variations in dosing, there may be a variation in how it's administered, but it should actually work for almost any inflammatory disease, which could potentially mean that it would be the gift that would keep on giving in terms of helping to save and change patients' lives. Financially. Yeah, thanks. I was rambling and I forgot. Yeah, financial position right now, we have sufficient cash to get through the end of this year and into Q1 2027, that cash will actually get us to the point where we will be able to at least start enrollment of patients. Thank you. That was James Rolke, CEO of Revelation Biosciences. Thank you, James. Yeah. Thanks for having me.