Great. Welcome back, everyone, to another session here at Oppenheimer's 35th Annual Healthcare Life Sciences Annual Conference. I'm Leland Gershell, one of the biotech analysts here on the research team. Really delighted to have with us Trevi Therapeutics, Jennifer Good, company's President and CEO. We'll be running through a few slides, and then we'll also have some kind of fireside chat back and forth for the remainder of the session. And please feel free also to lob in any questions of your own. As you may know, we've been covering Trevi for some time now. Really like the story, and the company is broadening its wings not only from IPF chronic cough, but potentially to a refractory chronic cough opportunity with upcoming data, and with that, I'll turn the podium over to Jennifer. Thank you, Leland, and I'll just run through seven or eight slides to tee up the story. It's a great time to look at Trevi. We've got two major clinical data readouts coming in the next few months, so make sure everybody understands that landscape before we launch into questions, so just starting off, Trevi is a cough company. We have a single asset now, Nalbuphine ER, and we are focused on chronic coughs of different subtypes. There's a significant unmet need in this area. There's been a lot of different therapies tried. We think what makes us unique is most of the therapies that have been tried and failed have been peripheral-only agents in the lung. My co-founder of Trevi is a neurologist, and he felt strongly that these coughs are really neurological coughs and that the right way to treat them was more at the brainstem. So we'll talk more about that. But we think we've got a unique sort of validated mechanism with our drug. We had very positive data in IPF chronic cough, a tough condition. IPF is an orphan-ish type condition, so it's got specialty pricing and a sales model, which results in a significant market opportunity. So here are the two conditions we've targeted as of now. We are in a Phase 2b in chronic cough and idiopathic pulmonary fibrosis. And as Leland mentioned, we've got a phase 2A proof of concept going in refractory chronic cough. RCC is a much bigger patient population, bigger opportunity, but I'll talk you through our strategy. We're really going to focus more on a specialty play here as well. We had phase 2A data in IPF chronic cough, big reduction. We saw a 75% reduction in cough frequency from study baseline in just three weeks, which was a 52.5% placebo-adjusted change, and you can see highly statistically significant. All the patient clinician reported outcomes were consistent and were stat-sig as well. Really compelling data in IPF. Back to the mechanism of the drug, which I think is sort of the secret sauce at Trevi. Haduvio works on the cough reflex arc that's important and controlling hypersensitivity along the pathway. Haduvio, our drug, is active in the peripheral nerves of the lung, which typically triggers cough in through the peripheral nerves in the lung. It travels up to the brainstem, which mediates coughing and breathing. The brainstem is also rich in receptors with our drug. It's active here, and we believe it takes away the worry about which peripheral receptors are triggering cough and why many other therapies have had a hard time separating because it's all going to end up at the brainstem anyway. We think of cough a lot like pain, which is mediated in the brain, a lot like itch. These are all tied together and all fundamentally hypersensitivity disorders. That's the underlying mechanism of our drug. Diving into our two conditions, the first is IPF and chronic cough within IPF. Idiopathic pulmonary fibrosis is essentially scarring of the lung tissue. It's progressive. It's an ominous diagnosis. People tend to live about three to five years from getting diagnosed. There's about 140,000 patients in the U.S. with no approved therapies. About 85% of these patients have cough. It's one of their number one complaints of the disease. It had become such that people had really stopped trying to deal with cough in IPF because of the progressive nature and the sickness of the patients and was considered really the toughest model to try to test cough in. We went into this area because of the mechanism I just showed you that we felt that scarring in the lung tissue was sending the signal to the brainstem, and that is where you needed to treat this cough. I'll take you into that data, but again, strong data. Cough is not just a bothersome symptom in IPF and other interstitial lung diseases. As you can see here on the right, there was a study that was done in this registry study. Essentially, over time, what you can see is time to first hospitalization. It's probably not hard to make the leap that if people are coughing 500-1,000 times a day, which is what these patients are, it's causing a lot of inflammation in the lungs. It can cause pneumothoraces, which are holes in the lungs, and just a lot of damage overall. This red line on this graph is severe cough. You can see that the more severe your cough is, the earlier you end up in the hospital or needing a lung transplant or even to death. Cough can be an ominous sign with the disease. Here's a snapshot of our data. I won't sort of drag all through this other than to show you that no matter how you measured sort of our phase 2 trial, the efficacy was strong. The upper left was the primary endpoint. The blue bars are drug. The gray lines are placebo. So 75% reduction as measured on an objective cough monitor. So people have a chest sensor and a cough monitor, measures their cough for 24 hours at baseline. And at the end, we had a 75% reduction in three weeks, 23% on placebo. And we also looked at 24-hour cough and roughly the same response. So this was an objective measurement, upper left. The bottom left is a patient-reported outcome. How frequently did you cough today? And you would hope that if it's going down on the objective cough monitor, the patient also can sense that. And indeed, that happened. You can see right away cough starts going down in the patient's judgment. And by day three, it is actually statistically significant. Another important point on this bottom left graph. You can see across the bottom line here, we were titrating up across our dose range from 27 milligrams, 54, 108 to 162. And off of this data, we concluded that most of the effect seems to come on at the lower doses. So as we talk about the 2B study we're in now, we've dropped this higher dose in the dose ranging study we're currently running. The upper right, I think, is actually the most powerful graph because this is a responder analysis. And what it tells you is this effect that you saw on the upper left was not driven by just a handful of patients. Actually, as a 30% change, which is considered clinically meaningful, every single patient but one had a clinically meaningful reduction. And as you raise that bar, cutting it in half, it's still three quarters, and a 75% reduction is still 41%. So worked in a lot of people. It was a big response. And the bottom right is just another way to look at cough in terms of cough bouts and counting. You know, as you might imagine, people don't cough linearly. They have these bouts, and that's where a lot of damage is done. Also highly statistically significant. So we are now into a Phase 2b study. It's 160 people, bigger study. It's two weeks of a titration period and four weeks of fixed dosing. So it's a longer study as well. I mentioned that we're looking at our three lower doses there, trying to figure out what we want to take forward in the pivotal study. This study is almost fully enrolled. And we had an important event in December. We had built in a sample size re-estimation, which we'll probably talk more about in Q&A, where we had an unblinded statistician take a look at the powering assumptions, confirmed our powering was appropriate, and we continued on at the original sample size of 160 subjects. So that was encouraging. We expect to report out the full results of this trial in the first half of this year. So this data is coming. The other indication we're looking at is refractory chronic cough, our RIVER study. And this is a competitive landscape chart. And sort of just to acclimate you to it, the further out is phase 1, phase 2, 3, and approval in the middle. So what you can see here is there's nothing approved. For those of you that followed sort of the Merck-Gefapixant story, that ended up getting rejected by the FDA. There were a lot of failures in phase 2A. Again, our theory here is these are all peripheral-acting agents. So there's only sort of one man standing left. It's Bellus Health, which was acquired by GSK. They'll report out data later this year and first half of next year. So we decided to jump into this arena because we think because of our central mechanism, we've got something to bring to these patients that they're not going to get with sort of current existing options that may come out of this space. So we're running a phase 2A crossover here. It's 60 patients come in on drug or placebo, wash out, and go to the other side. Across the bottom, you can see the same VitaloJAK reading, so same primary endpoint on 24-hour cough frequency. The last patient had their last visit in January of 2025, and we are going to be reading out this data in the first quarter, so it is exciting for the company, so just to close this out, we have got two significant near-term clinical milestones. Big unmet need in both IPF and RCC with no approved therapies in the U.S. We have got a unique mechanism that looks at cough hypersensitivity both peripherally and centrally. We have the best-in-class data in cough, period, and a positive sample size re-estimation on our current running trial, which de-risked that trial to some extent, so you can see here these two key milestones reading out in the first half of the year and also a strong balance sheet to go with it. We had at year-end about $108 million in cash. That takes us into the second half of 2026. Importantly, we will not need to raise money on RCC. We've got the money to run the next study if the data supports it. We will need to raise money at some point, assuming our IPF trials are positive because we plan to move forward in parallel pivotal studies. So with that, I'll stop and turn it into a fireside chat with Leland. Excellent. Thank you for that overview, Jennifer. So I think we'll start out with where you kind of left off on the SSRE, which, and this is not, you know, so people know this is not an uncommon approach to clinical trial design. You know, many companies have employed this as a way to, you know, do what is appropriate and then if they need to have to, you know, maybe expand enrollment because things may be a bit different than they had expected. So just kind of to back up to your original plan, you know, maybe if you could remind us kind of what the powering had been starting out and what the trigger was for the SSRE and there was no change. So presumably that means that things are going as you had expected. Yep. No, you're right, Leland. We put this in place because as you saw, no studies have been successful in phase 2. There was not a lot of powering information other than what we had in our phase 2A and some information from RCC. It was a way to protect the study. What we were essentially built into the sample size re-estimation is there is 80% power in this study. We were confirming the conditional power assumption. There's two pieces that go into that power assumption calculation. One is effect size. We assumed an effect size of 36%, a placebo-adjusted change. If you remember the data I just ran through, we had over a 50% placebo-adjusted change in a crossover design and then also multiplied by the variance. So essentially what the statistician did is confirm that we are at least 80% powered or better. And that's going to be some combination of effect size and variability. And so that's where we sit today. And as I mentioned, we're almost done enrolling that study. Yeah, that's terrific. We also saw the results of the human abuse potential study late last year. I think that, you know, but that seemed to clear up maybe concerns that some people had had with respect to the fact that this was a member of the opioid class. Maybe Jennifer, just want to kind of summarize where you are now with, you know, FDA, DEA. Is there anything you can comment there on scheduling? Nalbuphine is not a scheduled drug. So presumably that, you know, may not change. But, you know, we'd love to hear your updated thoughts. Yeah, no, it's a good question. So nalbuphine is broadly in the opioid class, but it's in a subcategory called mixed agonist antagonists, which were actually designed to deal with drug addiction way back when. So the drug blocks the mu receptor and agonizes at kappa. It's been around as a subcu injection in pain and has been unscheduled for decades. So that was a nice place to start from. Leland mentioned our human abuse potential study. We had to bring the data up to current-day standards because a lot of the work was done sort of way back when when the subcu was approved. So we ran our human abuse potential study. We reported that data out in December. It's still up on our website. And Leland's right. There was nothing in the data. Essentially, you have to compare to a comparator, which we did, which was Schedule IV. It's important people don't conflate. It's sort of, it's not Schedule II as everything. There's varying degrees of scheduling. And Schedule IV are things like tramadol, sleep drugs, et cetera, things people take pretty commonly. Nalbuphine is unscheduled. So the FDA wanted us to compare it as sort of the next schedule up, if you will. We statistically separated from our comparator. We were lower in all measures on the clinical doses. There was a supratherapeutic high dose, which was numerically lower, but didn't statistically separate. I think as we've been told by our experts, we'll submit all this with the NDA filing as part of an eight-factor plan. But they don't see anything. We don't see anything that really changes sort of how they've thought about this drug. They've been surveilling it for many, many years. It doesn't show up as a drug that gets abused, mostly because it will put people on opioid withdrawal if they take it. So we feel really comfortable with the data. We think the data supports its unscheduled status. And we're done for now. Essentially, when we file the NDA, it'll all go in. Great, great. You know, the CANAL data, obviously very strong. Some have made comments about the dropout, you know, rate in this study. Maybe just fill us in on some perspective, you know, there. Yep, so one of the challenges of CNS drugs in general and opioids specifically is you have to get the titration schedule right. There's always a bit of getting drug on board in the brain that people recognize, and some people bail out on it, even though the adverse events tend to be mostly mild to moderate, sort of 95% of any AEs we see. They tend to be also CNS and GI side effects, so things like nausea, headaches, some sleepiness, dizziness. The other hallmark of them is they tend to come and go in a few days, so three to six days is the average length of time, so when you run your first study, you don't coach the subjects a lot because you want to get a true read of what they're seeing. And to your point, Leland, in the CANAL study, the phase 2A IPF study, we had about a 14.5% discontinuation rate due to AEs. Going forward into this Phase 2b study we've just talked about where we had the positive SSRE, we've been able to take the information we learned and better prepare subjects. You may have some headaches. You may have this. If you have some nausea, take it with food. They don't last long. And our DC rates have come down into single digits. That's in total. I don't even know by drug or placebo. So I think as you move forward in drug development, you're able to educate the patient better and also give them some tools to sort of move through it. But it is sort of the flip side of the coin of, you know, a potent CNS active drug. People have to get used to it being on board, and then people do well on these drugs. It's why people can stay on opioids for years because they're a very safe class of drugs. Absolutely. So we look forward to the upcoming data in IPF. And how should we think about that informing, you know, remaining steps in development for IPF cough given kind of the dose ranging? Yeah. So the important part here is obviously to confirm. So hopefully the strong response we saw, we'll be able to select hopefully two doses to take forward. We're intending to go into an end-of-phase 2 meeting in the second half of the year. The team's already preparing for that, be able to have conversations with the agency about our pivotal program. Our intent is to run our two phase 3 programs in parallel, which we are preparing to initiate the beginning of next year. I think importantly, because there's such a large effect size here, these studies aren't much bigger than the studies we're running now. We don't anticipate they'll be a whole lot larger. So very doable and executable by us. We will need to gather one-year safety data. So that'll probably be the rate-limiting step here. The endpoint will probably be a three-month efficacy endpoint, but we will need patients to run out for a year of safety. So we're planning internally roughly a year to recruit these two studies, which is what we just recruited our 160-patient study in. So I think we've got good sort of benchmark there and then a year of dosing, and then we would be in a position to be able to file. Yep. Okay. Terrific. And the P2X3s have not shown supportive data in IPF cough. So presumably, you know, Trevi would really be kind of the first and only, you know, approval for IPF. Yeah. As of now, we're first in class, best in class. You're right. The Merck drug had worked in refractory chronic cough early and failed in IPF. And I think that's that peripheral mechanism. That's a high mountain to climb when you've got this progressive fibrosis going on. So yeah, we are sitting here alone in a big unmet need and a tough patient group. Yeah. No, and speaking of mechanisms, that kind of takes me into RCC, which is, you know, you clearly are centrally acting as well as peripherally. Obviously, the stimuli for the cough is different between IPF and those who are, you know, just simply have, you know, refractory chronic cough. As we think about kind of the, you know, likelihood of success in the RCC study, I mean, it seems like things are stacked in your favor. Would there be any concerns that one might have between IPF and refractory chronic cough that, you know, would make Haduvio less effective in RCC from the outset? So the KOLs in this space are watching our trial with a lot of interest because there's been so much work done on peripheral agents. And I think if we're able to show good data in IPF and RCC, it's very informative that this truly is a hypersensitization issue at the brain. And you've got to treat it at the brain. So we've already been asked to speak at a lot of different conferences and share our data. So we believe, Leland, that fundamentally it is back to this hypersensitization of the brainstem, and it should work equally across those two indications. I would just point out, though, as we move forward to this phase 2A, it sort of gets rid of any crazy placebo effects because you're your own control. They tend to not crop up here. Just as a warning, and we're certainly thinking about it, some of the bane of RCC drug development has not always been drug effect. It's been the placebo effect and getting the right patients in, making sure you, because this is an idiopathic cough. So you've got to make sure you've got RCC patients in. And fortunately, thanks to the work of others in the field, that sort of path has been laid out now about adjudicating the indication and doing a placebo run-in and some of that. So as we move forward, I do anticipate RCC's got some different challenges around placebo, but I expect our drug should do well across both indications. Yeah. Terrific. And, you know, with respect to RCC, presumably, so let's say you show good data there, so then you would in parallel be taking that forward in both, you know, RCC and IPF. Those are obviously very two different kind of market opportunities. I know it's early for anybody to be talking about pricing at this point, but maybe you could kind of lay out a bit in rough brushstrokes kind of, you know, what the, how the pricing might work given that you've got an orphan condition and kind of a non-orphan condition and maybe an RCC or strategy is to look at those patients who are sort of in the very refractory, you know, bucket. But please share. Yeah. Yeah. No, you're thinking about it the right way. I mean, so Leland's right. IPF, I mentioned 140,000 patients, 85% cough. The whole refractory chronic cough market is several million patients. And sort of when you walk it down to who has sort of moderate to severe refractory chronic cough, it's somewhere down in this two to three million patients. I think payers are going to be concerned, obviously, if you're pricing in sort of a more orphanish kind of pricing situation in that kind of size of market. So the way we think about it is that we are going to put restrictions up that really protect payers and get the appropriate patients to our drug. So as you referred to, Leland, really the most refractory patients. So, you know, you'll probably have had to fail at least one or two lines of therapy. So they'll fail all the stuff they take now and nothing works, and if there is a P2X3 approved ahead of us, you can work your way through that. We already know P2X3s only work on the most severe cough, so there's a whole moderate to low severe patient population that's not getting effective treatment from them, and then other patients who may just have so much cough, it's not getting covered. When you fall through that funnel and sort of focus on the specialists that prescribe that, so places we would be anyway, pulmonologists and allergists, you get down to about a patient population of about 200,000 to 300,000, so we've done a lot of market research. The pricing in IPF's pretty inelastic. The antifibrotics, which are there, are priced at $140,000 a year. So we played around with modeling this $50,000-$60,000 a year to be able to cross both of these. We've tested that in payer research in RCC. And with prior authorization and failing two lines of therapy, payers were very comfortable with that. So that's a strategy. And it does actually, it's not too early to think about it because it'll inform our clinical trial strategy going forward and which patients we bring in. Right, right, right. Good, and then maybe just to, you know, cover the kind of the patents of the IP around Haduvio in terms of protection in the market. Yep. Yeah. So as I mentioned, Haduvio is an old compound in a subcu injection form. We took it into a nice twice-day oral extended release. So we have three layers of patents. The primary layer that's probably most important are method of use patents around the indication and the drug. Those are issued. They go out to 2039. We also have formulation patents that are around the extended release aspect of the product. Those start to expire in 2030. And then we've got a bunch of what I think of as special population applications, how to dose an elderly, how to dose in hepatic impaired. Those are all applications that just create additional bricks of protection around your method of use patent. So we feel good about the protection we have around the product, and especially with nothing else in the market. Great. Good. We look forward to the upcoming RCC data, which is coming real soon, and also the IPF cough, you know, Phase 2b data. So lots going on this year for Trevi. Thank you, Jennifer, for joining us. And thanks to everybody who zoomed in for this session. Thank you. Take care. Thank you.