-the time by summarizing the incredible analyst event you hosted a few months back, because you just had to sit there and listen and have a full appreciation. You just spend that time, and you'd know pretty much everything you need to know about Trevi. Yeah. Maybe summarize that. Sure. To kick things off. No, at a high level, I think Trevi has been on a journey. We're in a unique place. We're a single asset company. We've got a mechanism we'll probably talk more about, work centrally and peripherally. We have found our way to the cough space, specifically IPF cough, ILD cough, and refractory chronic cough. It's been an interesting journey because as we've been working in this field over the five years, I think we've made a scientific breakthrough around, and kudos to my co-founder who's a neurologist. He kept saying to me, "People are thinking about cough as a lung problem. It's a brain problem." And sure enough, our central mechanism has put up very consistently good efficacy data, which is nice. I think the other dynamic that's gone on, I'm sure we'll spend some time talking about, is the field was very crowded when we got in. All peripheral- only mechanisms, all of which have failed. We are sitting in these three very big unmet need areas, and we are all alone at this point. We are into phase IIb and phase III, depending on the indication. We have got good alignment with the FDA, and I feel like it is a pretty clear path forward. We just need to execute. Okay, excellent. At the event, you laid out the design of the OCEAN-1 and the OCEAN-2 trial, and they are different designs. Maybe quickly summarize the design and then also explain why they are different. Yeah. OCEAN-1 and OCEAN-2 are the trial names we have for our IPF cough, idiopathic pulmonary fibrosis cough. For those of you that do not know, about 85% of IPF patients cough. It is one of their number one complaints of the disease. It is a big deal to the patient. We had run a very positive phase IIb study, went to FDA. Agreed with them on essentially one really robust, big study, which is a 52-week study. It has got a 24-week efficacy endpoint, and importantly, that study has 300 patients. Because of our big effect size, you do not need a lot of patients here. We ended up powering that study through all seven secondary endpoints, including things like dyspnea, breathlessness, which is the other complaint these patients have, clinical meaningfulness, all things that are robust in the label. In that meeting, the FDA suggested to us we consider running a second confirmatory trial, and this was in the era of Marty Makary saying everybody only has to do one pivotal. The division director said, "Look, we think it would be in your best interest to run a second study. It only has to be 12 weeks, not 24, and you only have to power through your primary and key secondary." That study is 200 patients, 12-week efficacy endpoint. The other study, the bigger study, is 300 patients powered through all endpoints, 52 weeks with a 24-week efficacy endpoint read. To be clear, we will not read that out till we unblind the full study. Got it. I am guessing we get probably similar questions from investors, maybe a little bit different, but one that has come up recently for me is the negative phase III data for camlipixant that many hoped would be positive. Of course, they had some design changes kind of towards the end there that did not set them up quite well. But obviously the question is, given that failure, should we be thinking any different about the prospects of success for Haduvio? We get asked the same question. How do you respond? That is the question I was asking everybody that I could get to. I did get some intel this weekend, so it is some hot off the press information. From Trevi's perspective, the only thing we really had to care about, the drug effect, I mean, obviously we care for patients, but did not really impact our program. There has been a placebo effect problem sort of that ran through the Merck program that I think Bellus/GSK did a lot of work to try to manage better. They made sure they truly had RCC patients in. They did some placebo run-in work, yada, di, yada. The news that we got this weekend, because apparently GSK has announced. They made an announcement in July that the trials failed, and they were terminating the program. Nothing else. They gave no other data. What we learned is that data has been shared with the investigators in the RCC study that were in their study, who are also now our investigators. The word through the investigator grapevine is it wasn't a placebo problem. Placebo was well-behaved. The drug just didn't work. I guess in one of the two studies, drug was actually worse than placebo. Not shocking that they didn't want to put out that data. They just, I think, pulled the Band-Aid off and moved on. We interrogated that a bit, that our assumptions are fine. Nobody seems worried placebo effect can't be managed. These were two 1,000-person studies. To be clear, our phase III, because it's an sNDA, we need one study, and it's probably only going to be about 300 patients. I think our ability to get the right sites, the right patients, we've implemented all the things that I think Bellus and Glaxo left behind as good learnings. We should be able to get through this, I think. Okay. I guess to maybe to emphasize multiple phase II trials all aligning on the same therapeutic effect, which is much more substantial than the P2X3 mechanism. Well, that's yes. Probably gives you a lot of comfort that- They have a minimal effect size, so any variability, you could lose that pretty quickly. Yeah. So. All right, another question I get that you may get as well from investors, probably the most common question I get is, "Why do I need to own the stock now?" I love that question because come back in a year from now, and you'll have the answer to that. When you get asked that, do you have a response? Yeah. It's funny, we just heard this question right before this meeting. Yeah. I guess what I might say to that is we start having news. It's been a little bit of a quiet window, but we start getting news. We're going to have an FDA meeting later this year, fourth quarter, around our ILD program that's going to cement that program. I think that's not in a lot of people's numbers because there's a lot to learn there. We're going to have our sample size re-estimation in RCC by year-end, so that'll be the first data readout. Then second half of 2027, we have two major data readouts. We have that OCEAN-2 study, which is the 12-week study, will read out in its entirety, and the full RCC study will read out second half 2027. Now, I can tell you enrollment's hustling along in RCC, so can we do better than that possibly? My comment to everyone is I get that, and I don't really care when people buy the stock, but good luck gaming out when that exact moment is. Because starting later this year, I do think things are going to start heating up again around Trevi. So buy it when it works for your fund, but hopefully things start moving along later this year. A topic that often comes up alongside this question is potential strategic interest in Trevi that could, in theory, emerge at any time. I know there's only so much you can possibly say to that, but maybe on a more pointed question basis, do you feel like the negative data for camlipixant may push potential strategic partners to wait till after phase III as opposed to moving before? Yeah. I think it's a valid question, [Josh]. We're obviously in conversations with everybody who's interested in this space. A lot of companies have tried at cough. I do think though, and this is probably a CEO's perspective, if I'm a CEO and I've bought a phase II asset for a lot of money and it's blown up in phase III, I'm probably not doubling down on that bet. I'm going to just pay more and wait to de-risk it clinically. I would say from our perspective, we love that. Right. We've got the money to get through our trials. I think our team can run these cough trials as well as anyone. We're rolling. I think if we want to optimize value for our shareholders, we definitely would like to get through the data readouts. To be honest, we're gearing up internally to launch this. A la Verona, a la Insmed. You can do respiratory launches successfully. All right. Excellent. You mentioned the phase II dose-finding study for refractory chronic cough, the LAKE trial. Why would this be any different than IPF as a central mechanism whereby you may require a different dose? What are your expectations there? Yeah. This is a really interesting conversation. When you think about IPF or interstitial lung disease, they are all in the same bucket. There is a progressive fibrotic component in the lung that we believe is sending a trigger and creating the cough. There is a physical trigger going on. RCC is a different animal. The KOLs will describe it as hypersensitization. Essentially, you have started coughing, you have coughed so much that threshold in your brain has gotten lower so that everything triggers it. Smells, climbing stairs, talking. There is a belief that you may be able to get. Our drug is going right to where hypersensitivity is managed. It may flip a switch there, and you may need much lower doses. There may be an ability to down- titrate over time as that threshold resets. There is actually a biological argument of why you may need less dose. Now, we will see. Our phase IIb will answer that. We may be in the IPF dosing range, but if we end up in the low end of that dose range, we are doing a lot of work here on low-dose formulations, which could push us into, first of all, totally new IP, and second of all, you may be able to pursue some kind of second brand here. I was just going to ask about [open]. That is- m aybe we will jump to that and cover that now because that is, again, obviously a very common question from investors. How on earth do you reconcile an IPF- Yeah. -more orphaned market price with RCC? One way to do it would be a different brand. That would be very beneficial, I'd imagine. Yeah. In the absence of a separate brand, how do you reconcile it? Yeah. The strategy, and we had to come to grips with that when we started investing in RCC because you don't want to obviously be working on a program that's going to blow up your commercial model. [Josh] is right. In IPF, pricing is very inelastic. It's a rare disease-type population, and ILD is the same dynamic. We've price-tested this range of $75,000-$125,000. Basically, you can pick a number in there. It's very inelastic. RCC is a different animal. Glaxo had been giving guidance around sort of $15,000-$20,000 a year. What we had always said is that we would essentially, and we've tested this with payers, we would pursue a treatment-resistant population. You can fail two other lines of therapy, whether it's things off-label. People are using codeine cough syrup, gabapentin. They've all tried those now. That's one sort of step at it to a payer. The other step at it is you're seen by a specialist, so pulmonologist, which is who we'll be seeing for IPF ILD. When you take the RCC population, which is roughly 2 million- 3 million patients, and you step- edit it down for you've failed two things and you've gone to a pulmonologist, that gets you to about 650,000- 1 million patients. When we price-test that, payer said, "No, we will cover that." You've got step edits in play. This is covered. Now, the crazy part about that is there's now nothing left that works. Everything's failed. With 20,000 patients here at $100,000, this is a $2 billion drug. That is just such a massive opportunity that I think it's something, [Josh], we're just going to have to continue to work. Because although we sort of say we're going after this very specialty treatment-resistant population, that could blow up quickly because it's an aggressive group of patients who have not had therapy. It'll be something, but that's the commercial strategy we'll pursue. I would imagine, the numbers get really big- Yeah. -really fast to the point that, payers at some point have to start pushing back. I would imagine the way that you navigate through that is through discounts and rebates s o that you're not breaking their banks as you're still able to grow. I think that's right. Dave, I don't know if you want to chime in here. He always hates it when he talks about sales getting out of control. No, I think that's right, [Josh]. Each vertical, when you think about Trevi, the total addressable markets are really significant, very exciting. You think about launch trajectory, particularly if the non-IPF ILD indication ends up being one study, those are going to launch pretty close together. The P&L really has a lot of firepower with those indications. How then do you think about launching into a very broad RCC market that may be a little beyond the scope of what a smaller company can do? On the other hand, we saw Verona launch into COPD within the [crosstalk] They're still seen at the same centers, [Josh], actually. There's a lot of synergy between all three verticals. We're targeting pulmonologists. I think Dave, you know these numbers better than I do, but I think we've assumed roughly 50-100 reps for the IPF- Yeah. -ILD launch, maybe another- Yeah. -25 when you add on RCC and pulmonologists. So very doable by a biotech company. Why don't we come back to the LAKE trial? Because, again, an area that I'm sure we're both getting a lot of questions around with the powering analysis update. Remind us the design and the powering criteria in the protocol and how that might change with the interim update. The important design change here is our first trial was a phase IIa crossover. What that essentially does is reduce variability, and it really manages the placebo effect. The key step-up that needs to go on now is running a true parallel- arm design across doses. That's what we're doing, 100 patients, four arms. We're looking at the same dose, 54 BID. We have in IPF, 27 BID, and 27 once a day. We're trying to get at what do you see in these low dose ranges or this low end of the dose range. To answer your question on powering, we've assumed about a 30% effect size. We saw 56% in our phase IIa crossover, and we saw roughly 36% in our IPF parallel arm design. Just to give you a couple benchmarks. We think we've been conservative, but that's why we built in the sample size re-estimation. Just to give you a frame of reference, Glaxo was guiding towards a 15% effect size that they thought was meaningful to this patient group. We're basically double the effect size there, so a lot more room to move. Okay. What are the options at that point of the powering analysis in terms of continuing the trial? Yep. So what happens at the SSRE, sample size re-estimation, an unblinded statistician outside of Trevi will look at all the unblinded data, and we will get one of three answers. Either they confirm that you are at your original powering assumptions, and you should just continue on as is. That is what happened in the IPF CORAL trial. The second answer is you are within what is called your conditional power range, which is between 40% and 80%. That is just about adding more Ns. So in the experiment, as we have set it up, we are at 100 patients as the original N. We can upsize an additional 50 patients, which I try to help investors understand. That to me is a win as well. I do not care if the study is 100, 125, 150. If we have got a drug that works, we are going to find it in there. The third answer we could get is you are below your 40% conditional power, which we have deemed as futile. So we will get one of those three answers back. I will tell you, having done this is my fourth time of doing this at the company, and the three prior studies, the conditional power that was there at the 50% readout was the exact power that was there at the end of the study. So it is a pretty good read on how your study is tracking. If the trial is upsized, what would that do to timelines for the top-line data? We have not quite sorted all that out, but at that point, [Josh], we are at full steam with all of our sites. An additional 50 patients is probably, I am guessing here, but three to six months. Maybe a quarter, yeah. Yeah. We'll get honed in on those numbers, but it moves pretty quickly. As we kind of toggle back and forth from IPF to refractory chronic cough, if you're in a situation where either the trial doesn't work for some reason, or you need to upsize for some reason, how do you think about that potentially reading through and extrapolating to the phase III results for IPF? Not sure if that's a question that you get asked. No. Obviously investors are paid to worry about what could go wrong here. I understand. I think our IPF data has been very strong, so I think our phase IIb is more indicative of what phase III should look like. I think a phase IIb failure in RCC, I'm not going to sugarcoat it, would be surprising to me. Yeah. I think it would make people be like, "Oh, how did that happen?" We'll just have to see. In the upsizing scenario where there is a signal, but the trial needs additional powering, that may portend a different product profile in refractory cough versus IPF, which brings us back to reconciling a price point not only for different patient populations, but now adjusted for effect size. Have you considered what the commercial implications of that might be? Yeah. Just one thing I would point out here, there's a few things that go into your powering. One is effect size, one can be variability, one can be discontinuation. There can be some different things going on. You may dump in another 20 patients, and it has to do with variability, for instance. Just to sort of caution on that. As far as effect size, I guess I might say that if we end up with an effect size, say an RCC of 20%-25%, and your effect size in IPF is 30%, I still think it's in a world where they have nothing. In a world where it's hypersensitization, if you can settle that down for a window of time, I think people will continue to do well. I think Glaxo got convinced that with any kind of benefit here, these patients are desperate. Not that I want to lower the bar, but I do think there's a lot of room to move from 30%. Is the price point that you're contemplating independent of the effect size? It kind of sounds like it is, right? Like whether it's 30% or 40% or 50%, you'll still kind of wind up in the same price range. Yeah, it's a good question. Just to be clear, what we price tested was our product profile out of phase II, which was a 36% effect size. Again, fortunately or unfortunately for patients, we're in a world where there's nothing else available. If you're a cougher in IPF, this is your only treatment that's available to you. I don't think it has a big impact whether the effect size is 30%, 28%. I think these are patients that are desperate for things. What it might affect is our share, and I would say in the numbers Dave referenced, we've been pretty conservative in our share estimates. Yeah. As you know, sort of assuming 20% market capture. I could see where that maybe would have a little more impact. You think about the benefits seen in the phase II trial. Do you find most patients kind of have a comparable reduction in cough, or is it more of a kind of barbell where you have a bunch of patients who may not respond well and then a bunch of patients who respond really well? Yeah. If you remember our responder analysis, I think 2/3 of the patients had a greater than 50% response, and it was like 40% had a greater than 75% response. We had a massive responder analysis. We're actually doing a very cool analysis now, which I think we'll end up sharing. I can't remember if it's at CHEST or ATS, of how many people got down to minimal levels of cough. We sort of defined this with KOLs, I think it's five per hour. Most of us could live with coughing five times an hour. It's a really low number, or it's a really significant piece of the population that we got down to this low number. I think to answer your question, it's not a barbell. The net takeaway from our efficacy data was big effect came on quickly in a very large percentage of the population. Got it. All right, another common topic of discussion is for the non-IPF ILD patient population. What we often hear from specialists is that those patients have an underlying inflammatory disease, so you treat the underlying inflammatory disease, and the cough goes away, and so there is not necessarily a large unmet need in that setting. But you clearly have a very different view of that. Maybe you can address that concern and maybe talk to the types of patients who have this condition who aren't responding adequately to- Yep. -to therapy. We have done some work in this area. The connection between IPF and ILD, for those of you that do not know, is essentially they all have lung fibrosis. Our patient in this space is you have lung fibrosis, and you have cough. I think to the question you are asking, [Josh], there are more people in non-IPF ILD, and only about 50% of them cough as opposed to 85% in IPF. Or have untreated cough, I should say. I think to answer your question, depending on what you have, there are ways. They use steroids and different things, and I think maybe some of the more mild patients get some relief. But we have heard from pulmonologists that they have more ILD patients with really severe cough they are not able to address than even have an IPF. I think there is a greater percentage maybe that get some relief, but I still think there is a lot of untreated cough in that population. Are there particular buckets of underlying disease that account for the proportion of the symptomatic coughing non-IPF patients, whether it is scleroderma or other? If that's known, I don't know. Okay. Yeah. So more to learn as we go forward. There are 200 underlying diseases there. But again, the commonality is fibrosis. I haven't heard as much questions around Haduvio being considered an opioid-type drug. Now, I'm not sure if it's because those investors had those concerns, just haven't come back to the story to hear it or beyond. But there may also be questions amongst strategics around being associated with, quote, "an opioid." I thought your analyst event did a wonderful job putting this question to bed. Maybe kind of frame why viewing Haduvio as an opioid would be the wrong perspective and also the extent to which you feel like you have been able to shift any concerns amongst investors or strategics to recognize that point. Yeah. It's a good question. I feel like I've been the Pied Piper of educating people on opioids. Nalbuphine is an opioid. It's just that not all opioids are Schedule II mu agonists. When you think of fentanyl, morphine, and I grew up in that world, so I'm very well-versed on all the problems there. But there's other receptors in the opioid pathway, and that's what was so unique about nalbuphine. Nalbuphine blocks the mu receptor, so it gets away. If you're actually a drug addict, it'll put you in withdrawal and works at the kappa receptor. The thing we had to understand as Trevi is what does a kappa receptor mean? Nobody had really studied it. So that was kind of our journey. When you think about things like naloxone, naltrexone, which you can now get in the drugstore to reverse opioid withdrawal, nalbuphine is a nal. It's because it blocks that mu receptor, and it's why it's been unscheduled for decades. We also ran a human abuse potential study that confirmed that it did not show this addiction properties. On top of that, we ran a very sophisticated respiratory depression study, which we haven't published yet. We had literally no respiratory depression signals in that study. FDA, from our perspective, is done with this question. The drug's been unscheduled. I think it stays unscheduled. You have to spend five minutes thinking about the opioid landscape and that not everything's fentanyl. That's a scary world. Yeah. Trust me, as I tell people, I'm not interested in being a CEO of that company. They go to jail these days. I feel really good. I think the beauty of opioids, and when Tom and I started this company, we were looking to get the good efficacy you get from opioids. They have good long-term safety and get away from addiction, and that's exactly what this profile is laying out. How do we think about the ex-U.S. unmet need for a product like Haduvio and some of the paths forward versus some of the barriers you might encounter? What was the first part of that? Ex-U.S., beyond the U.S. Oh, ex-U.S. Right. Yeah. Dave, you want to answer this? Yeah. No, we think about that, [Josh]. But I think importantly for us strategically, it makes sense to keep the pie whole. We do not want to partner ex-U.S. rights at this point in time. We do not need the capital, and I think, again, from a strategic perspective, it makes sense to keep the market in one place under Trevi's umbrella. We are also, MFN is still a wild card, so we do not want to impact U.S. pricing. The U.S. pricing opportunity is so robust, we do not want anything to impact that. Just focusing on the U.S. at this point in time. Is nalbuphine approved in Europe and ex-U.S.? It is. It's an injectable. I think we'll go ahead and get the drug approved. Whether we launch it is a different question, I think. A lot of that's going to depend on the drug pricing debate. If they all force us to have to choose, Europe's probably going to lose access to some of these drugs, unfortunately. Now, to what extent does the fact that nalbuphine is approved as IV or sub-Q- Yeah. Sub-Q injection. Does that impact how different countries may look at reimbursing Haduvio, you know? We've done some reimbursement work. I think fortunately, there's very little of it. You can't really cross over from the sub-Q to the oral. We have oral extended release. Totally different doses, totally different indications. Europe's tough, as you know, so it'll depend on the country. Yeah. Someone's going to have to do a lot of work there. Just to be clear, if we ever do decide to launch in Europe, that will not be Trevi. I sit on the Rhythm board, and I've watched how much work it is launching internationally. They've done a great job, but it's a big infrastructure, and we're not going to do that. We'll end up finding a partner. I understand the question you're asking, [Josh]. Yeah. I wouldn't say we have enough expertise to be able to answer it. Fair. In my mind, it kind of brings to light the absurdity of the European reimbursement that they would not treat Haduvio as a novel therapy, despite it obviously being novel, obviously addressing a huge unmet medical need. I know maybe this can be the test case that changes this at some point. Yeah. A lot of the cough expertise has been driven out of Europe. They've got these cough centers. They've really pioneered the field, and I don't have the heart to tell them, "You may never see this drug," but it's just the reality of if this pricing conversation keeps up, they're going to lose access to a lot of these new medicines. They can get them when they go generic. What about Japan? Is that a territory you feel you might be able to address? We've had a lot of conversations there, and there's been good interest in Japan around cough. Shionogi did a lot of work there. Yeah. I think at the right time, that could make sense. In terms of diversifying the portfolio beyond Haduvio, when is the right time to consider that? Yeah. We have a lot of internal debate. Mr. Worry Bead over here. Yeah. No, look, we are busy. We like a lean infrastructure. Again, the robustness of the launch, if these indications get approved, is really tremendous. So I think at this point in time, let us just stay focused and get the job done. We need to get the job done in phase III. We are filing IP around other attractive indications. There's a lot of legs here around this drug, I think, and there's a huge return for us on that. I don't want to tip my hand yet, but there are things that investors know a lot about, and I think we could bring something there. I think we may just stay home here for a while. I also remind people, anything we could afford would probably have hair on it, which means my entire development team would run to that side of the ship, being the scientists they are. We don't need them doing that for the next couple years. Even post-launch, if you think about the indication approval timelines, you're always going to be in a beat-and-raise mode, which is important. You're saying new indications outside of resp? No, outside of cough. Outside of cough. Yeah, not outside of resp. There are things outside of resp. Would you consider outside of resp? There are things outside of resp. There are. One example I will give you is lung cancer. There is a lot of cough there. Okay. But that is kind of the outside of respiratory. So we are looking at that, but there are some things inside of respiratory that are very interesting. I will just throw out as an example, bronchiectasis. There is a lot of mucus production. It creates a lot of cough. Okay. There is some data that indicates our drug could dry up some of that mucus production. So it is things like that that we are looking at and getting IP filed around. What I love is how straightforward and simple the Trevi Therapeutics story is. Especially the fact that we can cover so much territory in 30 minutes, and feel like we really have a good handle on [crosstalk] And lots of cash. $319 million in cash gets us through all the milestones. Dave wants his [crosstalk] I have to have. Yeah. We did it? No. Well-capitalized. Wonderful discussion. Appreciate it. Jennifer and Dave, thank you so much. Thanks, everyone, for coming out and tuning in. Thank you. Appreciate it.