Right. I think we'll get started now. Thanks, Lisa, for joining us. All right. Welcome to the Trevi presentation. Thanks for joining us. We have Jennifer Good, CEO of Trevi, and Lisa Delfini, CFO of Trevi. Trevi is developing Haduvio. It's now Haduvio for chronic cough. Maybe, Jennifer, you'd like to go into the whole story, and we can just go from there. Sounds good. I'm not going to do the whole story and see you all. Some of the story. Breathe a sigh of relief, but I'll do three or nine slides just to frame out Trevi. We're right on the cusp of a whole lot of data, which I'm sure Annabelle will sort of dig into, so I'll at least give you a sense of what's coming up, so our whole focus is controlling chronic cough, severe chronic cough. There's a big unmet need in these areas, and I'll take you more specifically into the two markets we're focused on. We've got a unique central and peripheral mechanism. Most people trying to treat cough have tried to do it only peripherally in the lung. We think the brain's an important component of that, which I'll take you through. We had very strong data in IPF, which I think sort of validates the whole thesis around the mechanism. This is an area, if you followed idiopathic pulmonary fibrosis, it is a rare disease, not ultra rare, but it is rare-ish. So it's specialty pricing, sort of a targeted sales model. So obviously, very good returns around it. And two really significant market opportunities, both indications we're working in are both north of $1 billion. So this is what our pipeline looks like. Our lead indication is chronic cough and idiopathic pulmonary fibrosis. We're in the middle of a Phase 2b. And we also have a Phase 2a proof of concept going in refractory chronic cough. Importantly, I don't normally talk about Phase I studies, but we have two key Phase I studies also going on in parallel, ones around respiratory physiology, ones around human abuse potential, which I know Annabelle will spend time asking me about, so just so we don't lose sight of them. I'm going to quickly show you the data. Our IPF chronic cough data that sort of backs all this up, we saw a 75% reduction in chronic cough, which was a 52% placebo-adjusted change. Importantly, this drug worked in everybody in the trial except one. I think we've got sort of the pathway right here. All the patient and clinician outcomes also were statistically significant and lined up. This is the whole genesis of the company. I am one of the two co-founders. If you look down on the bottom right, this is sort of how we describe it. Haduvio works broadly across the cough reflex, both at the kappa agonist receptor level and the mu antagonist receptor level. Those are both opioid receptors. Interestingly, because how this drug works, it's not a mu agonist, which is sort of where all the scheduling addiction comes in. It works at kappa and blocks mu, so the drug is unscheduled. We think importantly to the cough story, and you see in the middle there, endogenous opioids work broadly in the body, but these drugs work not only in the lung, they work at the brainstem, which mediates coughing and breathing, so you probably are aware, in cough, it's been known for a long time, things like codeine, some of the morphines, they all work in cough, so the pathway has been known. It's just there's been a lot of baggage, and the other drugs have not worked that well, so idiopathic pulmonary fibrosis, it's a big, significant, unmet need. It's about 140,000 patients in the U.S. About 85% of them have chronic cough. Chronic cough is typically present at the beginning of the disease and stays present throughout the whole disease. This is a tough diagnosis. Typically, people live about three to five years. There are some drugs that have been approved that slow the progression. They're called antifibrotics. These drugs are very high-priced. There's been very little innovation for these patients. The problem with the antifibrotics is they do nothing to improve the day-to-day life of patients. It really just extends their progression of disease. So I think that's where we come in. We think cough's important. Not only does it impact their day-to-day life, it's also believed to contribute to exacerbations, which land a lot of them in the hospital. It can also contribute to the overall disease. So not just a bothersome symptom. We think it's actually an integral part of the disease. I won't drag you through all this data, but just if you glance at it, blue is drug, gray is placebo, and the upper left was the primary endpoint, so that's where you see on an objective cough counting, 75% reduction in three weeks for these patients, so if you're somebody coughing 1,500 times a day, that is a huge reduction. The bottom left is patient-reported outcome. You can see patients right away could tell they were feeling better, and by day three, it was statistically significant. My favorite chart's actually the upper right, which is a responder rate, so 30% is considered clinically meaningful. That's the reference I made to everybody responded except one, and you keep raising that bar, and it's still very high responder rates, and then bouts also gets a lot of attention, so the drug just performed very well in this trial. We're now in a Phase 2b trial. It's a classic parallel arm design, six weeks, trying to get the optimal dose to take into phase three. It's the same primary endpoint, the objective cough monitor. And we will get more into this, I think, in Annabelle's questions. But we did build in halfway through this study a sample size re-estimation. So when 50% of the patients complete, we'll sort of recheck our powering assumptions. That comes up here in December. So we're right on the cusp of sort of getting a midpoint look under the tent here in December. Our other indication, refractory chronic cough, this area has been fraught with failures. There's been a lot of drugs studied. And you look at that big chart on the left, essentially, the further out you are, phase one, phase two, phase three in approval. And what you see, all those red dots are essentially failed programs in Phase 2a. And I think our belief is the reason so many things have failed here is they were all trying to attack this refractory chronic cough, which is really an idiopathic cough, through the lung only and peripheral channels there. I think what's unique about our drug, again, is not only are we peripheral, but we're also working centrally in the brain. And everything ends up at that brainstem eventually around cough. So you can see sort of through this whole mass of programs, really, there's been one program that's still alive and successful. It was, for any of you that followed Bellus Health, acquired by GSK for $2 billion. They're really the only program ahead of us. And we think we've got an ability here to be best-in-class data. We're running a Phase 2a proof of concept. This trial is fully enrolled. We'll actually report top-line data in that, in the first quarter, and so just to wrap it up, and then we can go to Q&A, so a lot of milestones coming. First up will be our human abuse potential study. We'll talk more about that. We'll have our sample size re-estimation on our IPF program in December. Our RIVER trial, which is our refractory chronic cough study, will report out Q1, and CORAL, assuming there's no upsize, which is our IPF trial, will be first half, so big unmet need. We think we've got a proven mechanism. A lot of opportunity here. Lisa's done a great job with our cash position. We have over $65 million, so we've got money into the second half of 2026, and we can read out all these studies. So that's the background. Great. So let's talk about CANAL for a minute. So that was a pretty dramatic response that you saw in this proof of concept study, 75% reduction. What are some of the characteristics of that patient population that got you most excited, that made you make that wholesale shift from itch, cough, other types of indications that could be potentially used or addressed with this drug to just cough? Yep. So Annabelle's referring to when we started off, we started off pursuing the different places that the pathway was prevalent in the body. One was itch, which we also had a positive trial. But the cough data was just so compelling. First of all, IPF's been a really challenging condition. With the exception of BI's recent readout, there has been no successful study in that patient population in 10 years. It's a really big unmet need. Cough is something that's been bothersome. As a matter of fact, most people had sort of walked away from even studying it because it was so challenging. So when we pored over our data, it was so compelling, had worked in such a big way. It just made a lot of sense for us, I think, to pivot onto that unmet need. The itch space had gotten a lot more competitive with big pharma. The cough space, based on that chart I showed you, had sort of fallen apart with a lot of failures, so it cleared up, really not a lot of competitors and really strong data, and that's what made us pivot into cough. OK, and IPF in general has been a very difficult indication to enroll in, and given all these failures, have you seen that speed up and the interest level change for IPF in general? So interestingly, IPF has sort of two components that we compete for the same patients. IPF cough, we don't really compete with anybody because people have left it. But we are competing with all the IPF programs, antifibrotic programs going on. So for those of you that have followed Pliant, FibroGen, BMS, BI, we all compete for sort of the same rarish patient population. Having said that, because our program really is focused on cough, it's a pretty short study, we've had very good enrollment here. And Annabelle, you followed us for a long time, but we've stayed pretty much right on track with enrollment. So you're no longer bugging me about that like you did two years ago. So I feel good about the value proposition. Right for two years. Yeah. I feel good about the value proposition we bring to these patients. But it is competitive because it's a small group. Great. So maybe we can talk about CORAL and what you've designed into this trial that's different from CANAL and what we might learn. Yeah. So I think the important thing here, CANAL was the Phase 2a crossover study I showed you. That was a crossover design. And everybody in cough starts there. There's sort of benefits and challenges of crossover designs. This is a true parallel arm design, three different doses. I think what we'll learn here, one we'll get longer data. That was a three-week trial. This is a six-week trial. We'll also figure out, I think, in more of a pure way, what's the appropriate doses to take forward. In the crossover design, when you went on drug, you started at the lowest dose over three weeks and kept going up. But what we don't really know there is, was the benefit due to time or dose. So I think in this trial, we'll hopefully be able to replicate what we saw in a longer setting and really be able to sort out the dose. Are there any special secondary endpoints that you're looking at that might help you understand how cough itself, I guess, contributes to the disease progression? It's a great question. It's probably too short because it's six weeks. But eventually, and probably more in our pivotal study, we will look at things like hospitalizations, exacerbations, FEV. We will measure that. It's just whether you can see any of that in six weeks is probably pretty short to do that. But we'll see. We'll look at what's there. OK. And then I guess we're going to get into the HAP study. But just in terms of opioids in general, we know opioids have, at least mu agonists, having an issue with tolerance. Do you think that there's any issue with mu antagonists or kappa agonists to have the same type of issue with intolerance or tolerance, rather, and then have an effect wane over time? Yeah. So one of the keys with opioids generally of dosing, and for better or worse, I've been working in the space for about 25 years. So you have to titrate these drugs. They're centrally active in the brain. They're potent. You can't just put people on high doses of it. They don't tolerate it well. So yeah, whether it's a mu agonist or a drug, you have to get the titration scheme right. I think what our drug brings benefit around is you don't have sort of the worries around scheduling and addictiveness and all that. But you do have some of the same GI and sort of CNS side effects. I think once you get the titration scheme right, you educate patients around it. Our IPF study now, we're seeing very low levels of people leaving the study, which is always a good sign. Most of the side effects are what you consider sort of tolerability things. They come and go in a short window. After the first week, they tend to sort of dissipate and be at placebo levels. It is something we have to be mindful of. OK. Great. So we are coming to the sample size re-estimation. So maybe you can explain why you felt it was necessary to do this and what are some of your outcomes? Yeah. You love talking about these different outcomes. I know. So let's talk about that. Just educating the world so no one's surprised. We thought it was important to do because there has not been any successful Phase II in IPF cough. There's been a couple studies run. They both failed. We had a small crossover design. So there was not a lot of information to power from. We looked to the RCC world. So we took some of our data to the RCC world. But in this space, you don't want to do what we all used to do, which is just throw an extra 50 or 100 patients in the study because there's not a lot of these patients. And that can end up dragging out your study. So we powered it based on sort of responses we saw. But at the midpoint, so 50% of the patients will complete, you have an ability to do what's called an SSRE sample size re-estimation, where an unblinded statistician outside of Trevi will look at all the unblinded data and rerun all your powering assumptions. So those are things like, what's the actual drug effect size? What's the actual placebo effect? What's the variability in the data? And if you need to upsize, we had to pre-specify a range that we were willing to do that in. That's an opportunity to do that there. So we'll get one of three answers back. Either your original powering assumptions were fine at our end of 160, carry on, or your drug is working, but you're going to need to dial in the end. And we have this pre-specified range of 160-400. So it could be anywhere in that range. Or you're outside of your range, and it's essentially futile. So we'll get that back. We get no other information. But you can sort of read a lot between the lines based on the answer. Interesting. As an FYI, I think I remember your proof of concept was 50, but then you halted enrollment at 40 because you already had reached statistical success. Yeah. That's the answer we won't get. Annabelle's right. We did an interim read on our Phase 2a trial I just showed you. And we were already stat-sig and basically stopped enrollment. We won't get that answer with the SSRE. If that's the case and we're already rolling along at stat-sig, we'll get the you're fine finish at 160. OK. And then just to talk about the patient population in this CORAL study versus the CANAL study, is it a different level of severity, same exact? Exact same. OK. Yeah. And we'll get to respiratory physiology, I think. But the only group that we've carved out, which is only about 15% of these patients, is really sort of the sickest of the sick, people that have sleep-disordered breathing. They're on CPAP machines. And opioids as a class has had respiratory depression associated with them. The mixed agonist antagonists, which is where nalbuphine falls, have not had that level of respiratory depression because of a ceiling effect on the drug. But it is something we're more formally studying. So we'll talk more about that. But that's the only group that's been carved out of both studies. OK. Specifically the sleep apnea. Yes. OK. Got it. All right. So let's talk about the HAP study. Because normally we wouldn't be that concerned. nalbuphine is not a scheduled drug. It's being compared to a scheduled, well, non-scheduled drug, Schedule IV. And you haven't seen any historically, we haven't seen any kind of likability towards nalbuphine. So why was this even a study that needed to be contemplated? Did the FDA change their criteria as far as likability? Why are they looking at this again? Yeah. So prior to 2017, there was a lot of preclinical data you had to generate to basically determine scheduling around your drug. All the work was done around what's called this eight-factor plan. nalbuphine's been unscheduled for literally decades. In 2017, the FDA, in the midst of the whole opioid crisis, put out new guidance for all CNS active drugs. So antidepressants, anti-anxiety drugs, opioids. So it was a broad class that you had to do these human abuse potential studies. So it's really just bringing basically the package up to current-day standards. And so what are the things that are being measured here and what are the criteria that you have to meet? There's a lot of endpoints, but it really is all around drug likability. So the primary endpoint is at the Tmax of the drug, how much do you like this drug? And so it's all drug liking. Would you take this drug again? Again, I think because of the mechanism, this is a mu antagonist. So think of naloxone and a kappa agonist, which tend to be more associated with dysphoric-type side effects. And neither of those have ever been scheduled. So we'll see. We're comparing to, as Annabelle mentioned, to a Schedule IV drug, which when you think about things like morphine, fentanyl, those are all Schedule II and highly controlled. And the reality of the world is it's either Schedule II or it's sort of everything else. There's a little bit of paperwork for the doctors. But things like tramadol, benzos, sleep aids, they're all Schedule IV drugs. So they're used for chronic conditions. So we'll compare to butorphanol. And either we are less likable and probably stay unscheduled. If you end up looking like butorphanol, there will be a discussion around whether Schedule IV makes sense. OK. Just to ask a really naive question, you talk about likability. You can like a drug for different reasons. You can like it because it's working. So I mean, what kind of patient are you putting this in? Yeah. That's actually a really key question. It is not IPF patients, and is your cough going down? I'm like coughing as I'm asking this. Recreational opioid abusers. They can't be on opioids at that time. But my best comp is they're like sommeliers of wines. They do these studies over and over. And basically, they have a sense of, I like this drug this much, and I like this drug that much. As a matter of fact, for them to screen into our study, they have to be able to delineate butorphanol from placebo and actually have a liking score associated with it. So there's sort of a little quiz before they get in that they actually can do that. So yeah, it's an interesting, weird study, but important. All right. right. And then just to go back, one question I forgot to ask you about the sample size. It's 160, or you can go up to 400. You can go up in increments, or are there set levels that you have to go to? No. The statistician will come back with an exact N. Now, whether they round to the nearest whatever it may be, but it's not sort of all or nothing. They will land us in the ballpark of where we're running to reinforce the original powering assumptions. OK. Great. And then, sorry, back to the HAP study. Yeah. I'm following you. So if you end up as Schedule IV, you mentioned it's like tramadol, various benzos, whatever. What kind of, I guess, perception do physicians have prescribing something that might be a Schedule IV versus something that has absolutely no scheduling whatsoever? I think in our IPF indication, it's really not relevant at all. A lot of these IPF patients are on Schedule II different things. They'll do anything to sort of manage this group. It tends to be sort of an end-of-life disease. In refractory chronic cough, which tends to be a little healthier patient population, I think when they're seeing specialists, their cough gets so bad, they end up in these cough clinics and things. We've done market research here. There's really no impact there. I think where you could see slower uptake and some impact is in the primary care part of this market. I think they'll just wait to sort of watch it for a little bit, but it's such a big market opportunity. It's two to three million patients, and if you're somebody who's been coughing for 10, 20 years, you're probably seeking out relief here. So there will be some impact in the primary care side. But it's such a big opportunity that I think there's still a sizable market for the drug. OK. Great. The respiratory challenge, really quickly, because I do want to move on to RCC, which is the bigger opportunity. So with the respiratory challenge, that's strictly to be able to possibly enroll a sleep apnea population. Is it something that you would see for Phase III? Do you need it for phase three? What is the purpose of it? Yeah. So we've been carving out this patient group just because we wanted to get proof of concept. The FDA had asked us about the respiratory depression. And there had been some back and forth with them about how you try to monitor that. It's almost impossible in an outpatient setting because it probably doesn't show up in these patients until they go to sleep at night. So there had been some discussion about keeping them in the doctor's office, yada, yada, yada. So after sort of going round and round with the agency, we just decided internally it made sense for us to run a proper phase 1 study where we'll bring in roughly 16 to 20 patients. We'll house them for the nine days. We'll take them across the whole dose range. We've got a nice monitor on monitoring sort of what's going on with their respiration. To your point, it's open label. We'll see the data along the way. The study's up and running. We want to have that data as we finish up this trial. When we go to our end of phase two meeting with the agency, we're able to hopefully, if the data supports it, convince them that we can now have this be an all-comers trial. Coming into phase three, we've got a defined patient population. OK. Great. Now let's talk about the RCC trial. Because refractory chronic cough, it's not a sick population. It's got idiopathic cough. So right now, you're moving into a proof of concept, and can you just give us some ideas of how this was designed and what kind of answers you're going to get or data that you're going to get from different parts of the population? Yeah. So it's a two-way crossover design, just like all the cough trials that I showed you and just like the IPF trial we just ran. What we'll know here is, does the drug work? I think importantly, one of the things we're trying to tease out here is part of the sort of history that's developed in refractory chronic cough. I mentioned to you, only Bellus is still sort of alive here. And I think what they understood about their compound, which really only works peripherally in this P2X3 sort of chain, is that they only worked on the most severe coughers, which they defined as greater than 20 per hour. It's not really a medical sort of view on that point. I think it was more of a statistical line. FDA didn't love that because people don't walk around with cough counters. How do people know if they've coughed 15x an hour or 20x an hour? But that's how they defined it. Because what we saw in our IPF studies, it didn't matter what your baseline cough counts were. We work broadly across all cough counts. And I think, again, that's back to the central mechanism. So to your point, Annabelle, I think the only difference from a typical crossover is we have stratified the population to have this 10 to 19 group, 10 to 19 coughs per hour and greater than 20. Because we're trying to understand when we move into Phase 2b, can we open the gates and include everybody as opposed to what Bellus has had to do, which is only enrich for the most severe coughers. So we will get that data as well from the study. You're statistically powered to show or you're powered to show statistical significance for both groups? We are. Those are exploratory endpoints. So the overall primary endpoint is the overall N of 60. That would only need a 25% placebo-adjusted change to be successful. But each of those arms that are exploratory with a 34% placebo-adjusted change would show stat-sig. OK. So this is a pretty large trial. And it would be for a very broad population. So what are some of the strategic ideas you have going forward? And maybe, Lisa, you can pipe in also. Obviously, IPF is a very rare condition or not very rare, but rare condition. And then it's got a different price point than what you would see for a refractory chronic cough, which could hit millions and millions of patients. How do you balance the two if it turns out that RCC is positive? Lisa, you want to answer this? Why don't you answer the strategic side, then I can answer some of the money side. OK. Fine. Fine. Fine. No, it's a good point. I mean, they're both big unmet needs. And it's something we sort of fretted about in the beginning and then realized it's a high-class problem if you've got the best answer in two big conditions. We are very committed to driving IPF forward. And there's a lot of good business reasons why that makes sense. We can handle it, high price point, big unmet need, sort of no competition. I think if we have the high-class situation where RCC data is also strong, as Trevi, assuming it was us actually launching it, we would focus in on more of the specialty markets, the pulmonologists, the other specialists. And we would probably actually become third-line therapy. You can go take anything else, your P2X3. And when it fails, you're going to end up on our drug. But you're going to be at the higher price point. So that's how we're thinking about it. The other option business-wise is maybe to do some kind of co-promote with somebody else and then try to manage through the pricing situation. So that's how we think about it now. We'll develop it as a specialty play for the most severe coughers that have failed everything else. And Lisa, maybe you can talk about the money side. Yeah, on the money side, so as Jennifer said, sort of we'd be committed to running the Phase 2b in RCC, and we have cash runway into the second half of 2026, so we have runway to go ahead and get started on that trial or the IPF trial, but we would raise money to fund the balance. Maybe just give a sense of what the total of both of those programs is, because it's financeable. Both of the programs is going to run between $125 million and $150 million. Both programs. Yeah. Yeah, so the Phase 2b in RCC and two Phase IIIs in IPF. So that's what we're sort of looking at. So keep your bankers busy. Keep the bankers busy or the strategic for strategic reasons. I guess, speaking to that, have you gotten inbound interest in these programs? I would say IPF has a tremendous amount of interest strategically in the industry. I mean, that's an area because of the specialty sales model. We are talking to people about that, and then you saw the chart. There's been a lot of big pharma who have tried to develop their own RCC drug and have failed, so also a lot of interest there. I would say this set of data we're going to put up is very important. It not only de-risks two sort of phase one questions, but gives you two sort of efficacy reads, I think, that matter a lot. So yes, we are in conversations. I think people are waiting to see this data, and we'll see where it goes. But I think this whole next step, we certainly can do it. We will keep moving along until someone shows up with a check that makes sense. OK. And I guess not to get too granular right now, but are they more interested for the RCC component, given that there's potentially only one player there with something that could only hit part of the market? Or is it something that is IPF more of an attraction for them, given that nothing's worked there? I would say it's both. It depends on who's at the table. There's certainly RCC-focused companies, but certainly a lot of multinationals focused in IPF, too. So I would say it just depends on who you're talking to. OK. Great. And then I guess finally, well, I think we've dropped anything related to itch, I believe. Yes. You made me do that in Newport. I made you do that in Newport. Exactly. Yeah, we do have a successful sort of Phase III in prurigo nodularis. That sort of sits out there. The problem is the pricing question you just asked me gets even more complicated when you throw in a whole nother indication, so Annabelle convinced me in Newport to just stop talking about it and leave it to the sun. I brought it back up. Yeah, we brought it just to make sure I didn't change my mind. I want to make sure you don't change your mind. Yeah. OK. Great. Well, I think that's it. Good. Very exciting. We've got some data coming up. So look forward to seeing it. Great. Thank you. All right.