Good morning, everyone, and welcome back to another session here on the morning of our second day of Oppenheimer's 34th Annual Life Sciences Conference. I'm Leland Gershell, one of the analysts on the Biotech Equity Research Team, very delighted to have with us as our next presenting company Trevi Therapeutics. Trevi is developing novel therapies for various chronic cough disorders, including IPF cough and also refractory chronic cough. On behalf of Trevi, we have the company's CEO Jennifer Good, who will be leading us through the presentation. If you have any questions, please submit through Zoom, and I will ask on your behalf. With that, I will turn the microphone over to Jennifer. Thank you, Leland, and thanks to OpCo for having us at their conference. We appreciate it. I'm going to jump right in. It's a good time to take a look at Trevi. We are a company that has a single asset, and we are focused in chronic cough conditions. This area has had a lot of attention from various companies over the last five years or so. There's also been a lot of failures. I think where we differentiate ourselves, which I'll get into, is we have a central mechanism of action that works both centrally and peripherally. I think a lot of the other competitors have tried to tackle this only peripherally, and we think that's a differentiator for our data. We have two indications that we're pursuing. Our lead indication is chronic cough and idiopathic pulmonary fibrosis. We'll talk more about that. And we're also doing a Phase 2 proof of concept in refractory chronic cough. Again, we think the connection between these two is there are essentially hypersensitization issues, and it's mediated at the brain stem. So because our drug is active there, we think we have a good opportunity to work in both conditions. In addition, we're doing two supporting clinical studies, which are important, I think, just overall to the label and the program going forward. We're doing in parallel some work around respiratory physiology and IPF. That's obviously a pulmonology impaired patient group. So we're doing some work around that just to define what the patient population will look like going into Phase 3. And because this is a central mechanism and an opioid specifically, we're doing human abuse potential studies this year, and we'll have that data later this year. The data that supports sort of jumping into chronic cough with both was a Phase 2 study we ran in IPF chronic cough, and I'll review that data in more detail. But just as a teaser, we saw a 75% reduction in daytime cough frequency for a 52% placebo-adjusted change. You can see the strong p-value of less than 0.0001. Also, all the patient and clinician reported outcomes were consistent and were statistically significant. So very strong data overall. So just a quick comment on the mechanism. I'm one of the two co-founders of the company. I co-founded it with a neurologist. This was a drug that we had been working on in a prior company we were both at. We were interested in it, I would say, for a couple of reasons. First of all, it's got a dual mechanism. So it works at both the kappa and mu receptors. This is broadly in the opioid class, but it's a subcategory called mixed agonist and antagonist. These drugs were designed to get around drug addiction issues, and this drug is indeed unscheduled. It's unscheduled when you think about things like morphine or fentanyl. They're all mu agonist. This drug actually blocks the mu receptor and agonizes at kappa. So it's kept the drug unscheduled sort of these many years that it's been available as a subcu injection. Also, I would say from my co-founder's perspective, who's a neurologist, he liked the interchange going on between the two receptors. He thought it was important in various non-pain indications. So if you slide right on this slide, just to point out where this drug's active, you know, obviously in the brain, we all know opioids work in the brain. Also, the brain stem, which becomes a key part of this story. The brain stem mediates coughing and breathing. And as I say, you know, no matter what triggers cough in the body, all roads lead to Rome. It all ends up at this brain stem, which is why we think we have such compelling data. In addition to the central mechanism, though, the drug does work peripherally in the lung and in the lung as well. So anyway, we think it hits both receptors and has an ability to bring some good relief. We've studied this drug over the better part of sort of nine or ten years. We've got a lot of data on it. If you focus in the middle of this slide, we've dosed it in over 1,100 subjects. We've got 270 subjects that have been dosed to six months and almost 100 subjects dosed to one year. We've looked at it in a slew of very severe conditions. I will note we've had positive data in all these various conditions: IPF, hepatic impairment, renal impairment. We have not seen any safety signal to date, so that's good. And the other question we get, we sort of answer on the right side of this slide, which is, do we see tachyphylaxis, or how is the durability of effect? And what you can see here is in three different studies, we studied this drug for a year or up to six months, and the middle one was six months. You can see at a fixed dose, there was good durability of effect over the long-term dosing of the drug. So the opportunity in chronic cough is a big one. There's a lot of underlying diseases that have chronic cough associated with them. That is a neurological reflex that's responding to some of these diseases. Specifically, we are focused on idiopathic pulmonary fibrosis and refractory chronic cough. But, you know, there is a whole big world here, and it's estimated to be about a $10 billion opportunity. This is a competitive chart for our two indications. And if you just focus on the left here, just to orient you, this is all the different drugs that have been tried in IPF chronic cough and their mechanisms. As you get closer to the center of the circle, the dark blue would be an approval. You can see nobody's made it that far. It's been a lot of drugs that have failed out in sort of this Phase 2 proof of concept space. We are actually the only company that's had positive data in IPF chronic cough, and you'll see that data in a minute. So we think in IPF chronic cough, not only can we be first in class, we think we'll have best in class data. When you look at the refractory chronic cough space on the right, you can see many, many companies have studied this indication and, again, failed in this Phase 2 proof of concept. Big companies like GSK, Bayer, Shionogi, been a lot of sort of failures. There's really two that have made their way into this inner circle, if you will. They're both P2X3s. One is camlipixant, which is the old Bellus compound bought by GSK. The other is gefapixant, which was the Merck drug. I'll get into a little bit of an update there, but gefapixant got a complete response letter in December, so it's not clear of the fate of that program. GSK is running two pivotal studies in parallel, so they are really the only competition we see in this space. And again, we think with our central mechanism, we bring a different option for patients. So let's talk about each of these indications. IPF chronic cough. First of all, idiopathic pulmonary fibrosis is an end-of-life disease. The prevalence in the U.S. is about 140,000. There's an incidence of about 30,000-40,000 a year. One of the hallmarks of this disease, besides being end-of-life and sort of a 3-5-year lifespan, is about 85% of these patients cough. It typically is one of the first presenting symptoms. It often is what takes a patient into a doctor's office to figure out what's going on. The cough stays present throughout the whole disease and typically worsens. This can become a very severe cough. You can see on the bottom left here, we show this can be up to 1,500 coughs per day, and I think the median number of coughs is 2,000-5,000. So, you know, this isn't just a little cough that comes up periodically. It's pretty serious overall. The other important thing, besides being one of the most bothersome symptoms of the disease, is there's a lot of growing momentum around that this cough is not just a bothersome symptom. It's actually contributing to the overall disease. So it's got this mechanism that if you think about sort of the physical trauma of coughing on your lungs this many times, not only does it cause inflammation, it can also cause holes in your lungs, hospitalizations, exacerbations. So those are things we will be studying as we work our way through our program. This was our CANAL trial. This was our Phase 2a proof of concept trial. It was a randomized double-blind, placebo-controlled, 2-treatment period crossover. This is the classic design that's being done in all these cough studies. Essentially, subjects randomize on either drug or placebo. They're dosed for three weeks. They wash out, and then they go to the other side. The primary endpoint in these studies is that VitaloJAK Cough Monitor you see on the bottom right. So that's the same monitor that was used by Bellus, by Merck, by everybody else who's studied in this space. Our drug is an oral tablet that's dosed twice a day, and we basically, in this study, titrated from a very low dose up to 162 milligrams. These are the baseline on the left are the baseline characteristics of the population. It looks a lot like IPF population. We had about 40 subjects in the study, mean age of about 74, and primarily male. About half this population was on background antifibrotics. So there are antifibrotics approved, which slow the progression of the disease. None of them have ever shown to treat any of these bothersome symptoms of the disease. So we think that these drugs will be dosed in parallel. What we saw from the half that was on antifibrotics, the half that weren't, was no difference in efficacy. You can see here the mean cough frequencies. Our primary endpoint was daytime cough frequency. It was 28 per hour, but a big range, ranging anywhere from 3-92. We also had a pre-specified endpoint of 24-hour cough frequency, which the numbers are very similar. On the right, you see the patient disposition chart. You can work your way down it. Essentially, we enrolled 42 subjects. 38 made it through at least one full treatment arm, and 28 made it all the way through the study. I would point out we did this study during COVID, which was challenging. There were twice that I can remember during the study we had to have patients withdraw from the study because the U.K. was on lockdown or various other COVID issues. So anyway, we made our way through with enough power that we were able to have statistical significance. This is the primary endpoint. This is that objective cough monitor I showed you measuring the mean change in cough. The primary endpoint was daytime cough frequency. You can see the 75% reduction on drug, 23% on placebo, for an overall 52.5% placebo-adjusted change. I mentioned we also looked at the 24-hour cough endpoint. It was pre-specified. Numbers are very similar. So, you know, this was a strong signal, gave us a lot of confidence. I think the other really powerful part of this story, though, is not only did we have a big drug effect, the other thing that drove that strong p-value is this drug worked in literally everybody but one subject. When you look here at this 30% clinically meaningful change, 97% of the subjects had at least a 30% reduction. When you move over to the higher bar of cutting your cough in half, in 3 weeks, remember, that was almost three-quarters of the patients. It was three-quarters of the patients. And you can see over on the right, the very high bar of cutting it by 75%, you still had almost half the patients. So again, that drove these strong p-values we show on the bottom right. It was a big effect, and it worked in virtually everybody. So that was the objective cough monitor. This slide shows you the patient-reported outcomes. So patients were doing a daily diary on various things. Upper left is cough frequency, how frequently did you cough today. Bottom left is how severe was that cough. Upper right was around breathlessness scores, and the bottom right's a clinician global impression of change. What you can see here from the blue line, which is drug, and the orange line, placebo, is the drug always separates from placebo, and it happens very quickly. So all these endpoints were statistically significant. I think the other sort of important thing to point out here, because it's really the launching point for our next study, which is this drug worked very early. This was actually statistically significant by day 2 at the lowest dose of 27 milligrams. So we, as we move forward, I'll show you, have decided to drop the highest dose, and we'll again study three different dose arms: 27, 54, and 108. Just to touch on the safety part of this, and I told you upfront, we've studied this in over 1,100 subjects. Every single study we've run essentially looks the same. They're typical sort of opioid-type side effects. You can see nausea, fatigue, constipation, dizziness, somnolence. You can work your way down. I think a couple hallmarks, 95% of these AEs are mild to moderate. This 1, 2, 3 is a grading system. And you can see most of these adverse events are considered mild or moderate in effect. And the other sort of important aspect of this is they tend to come on upon initiation of therapy. So remember, we're titrating this drug. So in week 1, these subjects were all on the lowest dose. As they move along, they get used to the drug from a just tolerability perspective, and they essentially have as you go out. And as you get out into these long-term studies, these AEs really don't rear their head. So it's something you have to work through in the first week. It's why we titrate the drug and do a lot of patient education. I think the other important aspect you can see across the bottom is that they tend to last about 3-6 days. So if someone has some nausea, they have some dizziness, headaches, they tend to come and go relatively quickly. So we've just started at the end of 2023 the CORAL trial. This is a Phase 2b dose-ranging study. I showed you in the data that it appears as drug effects coming on at very low doses very quickly. So we're doing a proper sort of parallel arm design here with 3 doses versus placebo. We're using the same VitaloJAK Cough Monitor as the primary endpoint. The overall study is only six weeks. You could tell from our prior data, we got a signal very early, so we don't feel this study has to be long. So it's a parallel arm design. Primary efficacy endpoint, no change from the prior study except we're using the 24-hour cough frequency. Important aspect here, we are going to just recheck the powering assumptions when half the subjects finish. This is called a sample size reestimation. So we'll have an unblinded statistician external to the company recheck the powering assumptions. We'll essentially get information back. It's pretty limited, but it says, you know, either your assumptions are fine, keep going, your drug is working, but you need to increase your N a little bit, or you're not going to fall within your conditional power range, and you should consider stopping. This is a helpful check, especially when you don't have a lot of data to power from. We had one study and not a lot of work in IPF. So it's a good midpoint check, I think, on how the powering assumptions are around the study. Various secondary endpoints, most of which we had in the prior study as well. So moving into refractory chronic cough, this is our RIVER study. This is a big problem, and many investors have heard about this space because people have been trying to crack this nut. It's estimated that about 5%-10% of the global population will have chronic cough in their lifetime, chronic coughs defined as a cough that lasts greater than eight weeks. Refractory chronic cough specifically typically has an underlying condition of asthma, GERD, postnasal drip. Those diseases get treated, and then coming out of that, they have this lingering neurological cough. And again, they refer to it as a hypersensitization. So things trigger it like exercise, talking, perfumes, you know, things like that. So this is something these patients live with. It's quite a severe cough. And you can see here, about 87% of these patients deem this to have a severe to moderate impact on their lives. So very disruptive. People live with it for years. You can see on the bottom part of the slide on the left, we've broken out of all these different cough frequencies. The gray is sort of the low cough counters and more mild, probably doesn't need some kind of chronic medicine. The high cough counters, which is greater than 20 per hour, is about a third of the market. But this moderate cough count, which is 10-19 per hour, is about 44%. And that'll be relevant as we get through to the story around the P2X3s we're competing against. So about 72% of these patients are uncontrolled. So it's a big market opportunity, big unmet need. This is a busy slide. I won't drag y'all through it. I think that there's a couple key things to point out. On the top part of this, I mentioned to you before, there's two P2X3s which are out in front of us, the old Bellus compound, camlipixant, and gefapixant with Merck. If you slide over to the middle here, you can see the placebo-adjusted change. Bellus in their Phase 2 study was a 34% placebo-adjusted change. Importantly, that was in an enriched cough patient population, so greater than 20 coughs per hour, and that'll become relevant below. They're now running two pivotal studies in parallel. Gefapixant had this pretty slim placebo-adjusted change. Indeed, if any of you followed the ad board at the end of the year, that drug ended up getting a Complete Response Letter based on the low level of efficacy. It's unclear where that program's going to go, but it's going to require another clinical trial. Just coming to the bottom, I think a really important part of this story is, although the P2X3s do work in some subjects, they don't appear to work in this 10-19 or below 20 cough counts. Merck put out data that showed it was not significant, and Bellus also, they didn't report the final results because it was statistically insignificant. So the P2X3s, which again are peripherally acting in the lung, so they're only catching triggers that come through that P2X3 channel. They've had to enrich for this high cough count to be able to get statistical significance. From our perspective, again, just taking you back to this graph where, because of our central mechanism and that comment I made that all roads lead to Rome, it doesn't matter what triggers cough, it's all going to end up at the brainstem, which is where our drug is active. We think that we can capture this moderate to severe cough counters, which is about three-quarters of the market. So we've set up our trial to be able to do that. So this is our study design. It's the same design you just saw for CANAL. It's a two-way crossover design. Subjects come in, they'll titrate up across our dose range, and then wash out, and they'll go to placebo. We're taking multiple readings with the VitaloJAK Cough Monitor along the way. I think importantly, if you focus on the right, we are doing this one-to-one stratification. So it's an N of 60 in the trial, but 30 subjects will randomize into these 10-19 coughs, and 30 subjects will go into the >20 coughs. We've powered the primary endpoint on the overall total population, the N, but we think that with a decent effect here in the sort of mid-30% range, placebo-adjusted change, we could see statistical significance on each of these arms, which would just be, you know, very game-changing in this whole space. Same primary endpoint, the VitaloJAK Cough Monitor, and various secondary endpoints. And last study, I'll just touch on quickly. Most centrally acting drugs have to do a Human Abuse Potential study. Opioids always have to do it. So we've been through a journey with the agency agreeing to sort of study design. Essentially, if you focus in the middle here, we've got a low dose, mid dose, and high dose of our drug. It's single dose. We compare to a comparator, which is butorphanol, and then versus placebo. And essentially, what you're trying to do is show that these recreational drug users can tell the difference of drug versus placebo and then determine if there's any difference in likability, so this drug liking at the peak max effect between these various doses of nalbuphine and butorphanol. Now, remember, I told you nalbuphine has been unscheduled, so that's where we start from. Butorphanol is Schedule IV, which importantly, when you think of a fentanyl or morphine, those are Schedule II compounds. Schedule IV, the DEA definition, is low likelihood of abuse and low likelihood of dependence. So, you know, we're comparing against a Schedule IV. The data, we should come out either less likable than butorphanol or similar, and then that puts you in this range of being either Schedule IV to unscheduled. So we've started that trial's underway. It's being dosed, and we'll have data in the second half of this year. So to pull this whole story together, we talked about the IPF dose-ranging study that's underway. We expect to have our sample size reestimation reported out in the second half of this year, data on the full trial in the first half of next year. Respiratory physiology will run in parallel. That's that we didn't talk a lot about that, but that's defining the patient population for Phase 3, so no time crunch on that. Our refractory chronic cough study is underway. We'll report that in the second half of this year, the full trial, and the Human Abuse Potential study will report out second half. So it's a big year of data for the company. Fortunately, we have plenty of cash. We have roughly $90 million the last time we reported it out. That will cover all these trials and give us a year past that of runway, so into early 2026. So that's the Trevi story, and I'll open it up, Leland, if you have any questions. Great. Thanks so much, Jennifer, for walking us through. Lots going on, Trevi. I guess, you know, maybe just to touch on sort of the one of the last points you mentioned about the human abuse potential. I mean, it is an unscheduled opioid. Is there a chance that there could be scheduling added since this is a new approval? How should we think, you know, about what the DEA could have to say about it coming, you know, to a label? No, it's a fair question, and I think there's always it's kind of a two-sided coin. There's always more risk when the drug's more available. So in theory, if you're going after these big indications with an oral formulation, it becomes more available. Scientifically, though, because this is an oral extended release, it's actually less abusable than the injection. So, you know, there's not a lot of reason to our molecule should be, you know, it's going to have a lower Cmax on the drug, you know, not that drug addicts can't do things to it, but we just have not seen in all our clinical data any kind of drug seeking, any kind of euphoria, any kind of likability. So we'll run the study. I think this is not a study I'm particularly worried about, but I think once we get through this data, we'll share it and can talk through what we think it means. Yep. Okay. No, that's that's fair. And, you know, I think we're looking forward to the RCC kind of, you know, proof of concept reveal that we'll be getting later this year. And you'd mentioned sort of the central mechanism of action of nalbuphine versus what's, you know, really more peripheral amongst the P2X3s. I mean, maybe just, you know, expand a bit. I mean, could it be the case that ultimately, you know, Haduvio could have a a broader scope of potential amongst people with RCC, given that presumably the mechanisms that lead to RCC in people out there, you know, are are multifold, right? So. Yeah. How should we think about, I mean, when these things sort of shake out in the marketplace, you know, maybe we could see, you know, maybe less of a scope of applicability for the P2X3s. Is that? Yeah. Something that we should think about? It's a super relevant question, and you're right. I think what's sort of the hallmark of RCC is there's a lot of triggers. It can be asthma. It can be postnasal drip. It can be GERD. There's a category called unexplained chronic cough. They have no idea what triggers it. So you're right that there's a lot of underlying etiologies. I think the fact that it all sort of ends up to the brainstem is helpful for us. You know, again, classic opioids, when you compare them to pain, it doesn't matter where your pain comes from, back problems, surgical, you know, all roads lead to the brain, and the brain sort of mediates pain. So I think they're very comparable. I would say sort of the hallmark of P2X3s is they don't work in everybody. They seem to only work in about a third of the patients. They only work in this enriched cough count. When you're focusing on only the highest cough counters and you're only getting sort of this 30-some% placebo-adjusted change, there's still a lot of cough left in these patients. So I think there's a lot of opportunity. We have also heard through sort of the cough grapevine, if you will, that the FDA is really struggling with this concept of enriched cough counters because, you know, the only way to get that is to strap a monitor on somebody and see their number of coughs. And so if it's really only working in the most severe coughers, which is 20-some%, that's not an easy thing to deal with clinically. You know, doctors aren't doing that when someone ends up in their office. So actually, over the holidays, Glaxo took those Bellus trials and upsized them by about 30%. We speculate here that that's probably in response to that question that's being asked, knowing that that's going to be sort of a discussion, but, you know, time will tell. Fortunately, in our data, in the IPF cough data, what we saw is there was that consistent response against all level of cough counts, low, moderate, and high. It's what gave us the confidence to stratify our trial and try to tease us out. Yep. No, terrific. And, you know, IPF, obviously, you know, drugs for the cough aspect aren't yet available, and you guys are kind of pioneering that. Obviously, there's two drugs that are approved, and there's some other, you know, work that's going on in the development space for IPF itself. And I'm not sure if you had touched on, but I think there is data to suggest that the cough itself could sort of accentuate or promote the progression of the disease, maybe just touch on what the evidence we have that may show that and how preventing or, you know, reducing cough frequency could be, you know, mitigating to that. Yeah, it's a really cool question, and we're excited about this opportunity because there's a lot of work, as you know, going on in IPF, which is all sort of these antifibrotics, the endpoints, FVC, improving FVC, which nobody really knows what that means to a subject. Also, those drugs really, people are still getting worse. They're just getting worse less fast. What we're trying to do is come at this from the physical trauma aspect on the lungs. And we think that can have ramifications. Not only the patient immediately feels better and can be out and doing things that are more normal, but you're taking that trauma off the lungs of the inflammation, the constant pounding on that. There's a lot of discussion among KOLs, and we're actually going to be doing some non-drug work to look at what's going on in the lung when this cough is happening, not only in IPF, but some of these other conditions. I think if we can make this link that we're not just treating one of the more severe symptoms, but actually the underlying disease, that's going to really change how this whole area is viewed. And you probably know, but antifibrotics are priced north of $100,000, so that becomes a whole different game. So we're going to be doing some of that work in parallel, and we'll look forward to sharing the results. There's a lot of interest among the cough experts in the work that we're doing around that. Great. Great. Maybe just lastly, you know, obviously, your work has been focused on the U.S. market, but, you know, there could be, you know, sort of global, right, chronic cough, whether it's IPF or refractory, is kind of a global problem. You know, anything to share with respect to your view on ex-U.S. partnering, you know, potential pursuits of those markets? Yeah. There's a lot of interest. We're always in, you know, conversations with sort of potential strategic partners around that. So a lot of good discussions in Japan and Europe. I think part of what we want to do is get through this round of data because this is going to be really defining, I think, about how this opportunity could be handled. We don't want to give up our rights in that yet. But, you know, if we end up commercializing, certainly probably not RCC, but we could commercialize IPF. We would only do that in the U.S. So, you know, depending on the commercial strategy, which indications we move forward with, we know who's interested here. There's been a lot of interest in these cough indications from a lot of the big pharma companies. I think once we get through the data and set our strategy, go forward, that'll really help with the discussions. Great. Well, we look forward to the news flow this year. Thanks again, Jennifer, for taking us through everything that's going on at Trevi. Thanks to all of you for zooming into this session.