Trevi Therapeutics, Inc. Aktie

We have some legitimate contenders in here. I'm going to tell you in 15 minutes, a quick overview of Trevi. So Trevi, we have a single asset, nalbuphine ER. We are focused in difficult-to-treat chronic cough conditions. For those of you that have been following cough, it's been a difficult area. There's a huge unmet need. I think what we've brought to the space is a differentiated mechanism that not only works peripherally in the lung, but importantly, centrally in the brain. We are the only investigational therapy that's had positive data in both idiopathic pulmonary fibrosis related cough, but also refractory chronic cough. So two big conditions people have been working in.

This is a specialty sales model. We are approaching it with a specialty focus that we can take this to market ourselves. It's got a big sales opportunity here. I'll take you through it, but it's about a $6 billion-plus peak sales opportunity. So our mechanism, this is where it all starts. The drug works not only peripherally in the lung, it works along the spinal cord and the brain stem in the brain. That mediates coughing and breathing. This is the whole cough reflex arc. So being present in that whole pathway is helpful. And to focus on our 2 lead indications of IPF and non-IPF.

So first of all, starting off with IPF. This is a terminal condition. It's about 140,000 patients in the U.S. You probably know there's been a lot of work done around antifibrotics, which essentially slow disease progression. We're focused on the patient, what upsets the patient's lives most drastically. And they talk about things like coughing, breathlessness, fatigue. So our drug is focused to lay alongside these antifibrotics and actually treat cough.

We estimate that about 2/3 of those patients have uncontrolled coughing, so about 100,000 patients. This is terminal. They estimate about 3 to 5 years of life expectancy. And a big impact on these patients. If you focus on the right, this was a natural history database that was done on these patients, and it maps cough. You can see the top line sort of more mild cough, moderate cough, severe cough and it's mapped against the time to first hospitalization, death or lung transplant. And what the takeaway message from this is the more severe cough, it's more of an ominous outcome around this disease.

So not surprising. You have progressive lung disease and then you're adding on sort of coughing of 500 to 1,000 times a day on top of that. That creates a lot of inflammation, stretch fibers, et cetera, which exacerbate what's going on. There's been different drugs that have been tried in this space. It's been a tough nut to crack. What all those red dots represent is sort of those different slices or different mechanisms that have been tried. We came along. We had the first positive data readout in this space.

The difference of sort of our drug, Haduvio and what you see in all these other pie slices, is those who are peripherally acting only. So they were working on one receptor in the lung. The problem is there's a lot of different triggers of cough. So what's unique about our drug is not only do we work throughout the lung, but we'll catch cough coming up to the brain as well. And that's been the difference.

I would also point out that antifibrotics have all studied cough and have not moved the needle there. They're essentially slowing disease progression, but cough is typically present at the beginning of the disease, and it stays present throughout the disease. So because you're not reversing disease here, the cough stays present throughout. So again, big unmet need that's not really served by the antifibrotics.

We finished last year a Phase IIb study, 160 patients. This was a 6-week trial proper dose ranging study. We looked at 3 different doses. The primary endpoint here is an objective cough monitor that counts the number of coughs, the key secondary is a cough severity scale. So how much you cough is one thing, how severe that cough is another. And then we have lots of other endpoints as well that we looked at. This data all did get published in JAMA, so you can go look at it. Just to summarize the efficacy data quickly on one slide. The upper left is the primary endpoint. So the gray line is the placebo effect. The 3 different doses, all statistically significant, and you can see a dose response there.

If you slide to the bottom left, this was the time course of this objective cough. We had a monitor on at baseline. We put one on at week 2 again, and you can see the entire effect was there by the first time we measured it. The upper right is a responder analysis. So we had prespecified 30%, 50%, 75% reduction in cough again, big impact for these patients. And if you just focus in the middle there, about 2/3 of these patients have their cough cut in half by the end of the 6 weeks.

The bottom right, the one patient reported outcome on this slide. It will be our key secondary in the next study. It's essentially the patient's assessment of cough severity and what you can see here is the green line is the 54-milligram dose, and this was consistent across patient reported outcomes that when you looked at it, the low dose just missed statistical significance and the high dose didn't add a lot on the PRO. So we ended up moving forward with the 54-milligram dose. So that's sort of a summary of the efficacy data.

The other side of that coin, the adverse events. This has been a very predictable drug. It works centrally in the brain. So you're going to see some of these different GI and CNS side effects. Nausea vomiting, dizziness, constipation. I think the hallmark here, if you focus on the bullets on the bottom, the placebo and the drug had similar discontinuation rates of about 5% to 5.5%. So not a big impact here for people staying on drug. 95% of these adverse events were mild to moderate. So people were able to work through them. The SAEs were actually lower in the drug arm. I think the key of why people stayed on drug. If you focus on sort of the dose groups along the top, most of these AEs occur upon initiation of therapy. So it's more about tolerability.

So we titrate this drug. We start low. As you can see here, as we were moving people up to the highest dose, adverse events are actually coming down. So we have a separate graph we showed last week at our Investor Day that typically these AEs last anywhere from a couple of days to about 9 or 10 days. So as people work through the first week or 2, they do just fine on the drug.

So moving forward, we had a very constructive meeting with the FDA, our end of Phase II meeting. We got very clear guidance out of the agency. We are running 2 studies, OCEAN 1, OCEAN 2 Essentially, we'll start off with our titration window. The first bigger study will go through 52 weeks of safety, so 54 weeks in total. I mentioned to you, we're moving forward the 54-milligram versus placebo. It's a 2:1 randomization. And then we'll track patients 3 weeks off a drug.

We also are going to do a second confirmatory study. We only need to look at 12 weeks there. I should mention in the first study, the bigger study, the primary endpoint will be at 24 weeks. So this is obviously answering the durability of effect question. The second study, OCEAN 2, will be a 12-week study. It's a little smaller. It's a couple of hundred patients, and I'll show you in a minute why that is why it's smaller than OCEAN 1, but we'll start that study in the third quarter of this year.

So just a time line around this. OCEAN 1, we're starting this quarter. That will run. It will read out the first half of '28, although there's a 24-week efficacy endpoint, we're not unblinding the study until the end. OCEAN 2 is a 12-week study will start in the third quarter. That will read out second half of '27. I think just some details on the bottom. You can see sort of roughly 80 to 90 sites in the U.S., Canada, Spain, Poland, U.K. We're really focused on U.S. enrollment here. OCEAN 2, same thing, about 70 to 80 sites. So we are in the throes of things of starting up all these sites and getting the study going. Primary endpoint is the same as what I just showed you. It's a change in baseline using the objective cough monitor, 2 different time points I mentioned to you.

And then on the right, this is important. We've actually powered in the bigger study all the way down through these 8 secondary endpoints. So there's a lot of things further down around breathlessness. We saw some good data cough out clinically meaningful changes. So we're trying to, on the bigger study, really get all of that into the label. The second study is just confirming the primary and key secondary end points. We're also going to add on to this. So IPF is about half of the interstitial lung disease market.

The other half consists of several different diseases. But what they have in common with IPF is they have lung fibrosis and they have cough. So when you go in and add on that other piece of this, this grows to about 350,000 potential patients. From our perspective, it's really the same patient. They have a lot of comorbidities, RA, Sjogren's, all kinds of different indications, but we're not treating the comorbidities. We're treating their cough in ILD. There's a tried and true path here from the antifibrotic work. Once you get IPF, you establish your dose, get that set up. You can do 1 trial in ILD and you can add it into your label. So we're going to go talk to FDA in the third quarter about that and look to initiate a study later this year.

Refractory chronic cough, which is the third leg of the stool here. For those of you that don't know this disease, there's no FDA-approved therapies. There's been a lot of drugs tried here. It has a really high impact on the patient, not surprising people. I mean, on average, these people cough 1,000 times a day. So a lot of anxiety, depression impacts their work and nonwork activities, and 2 in 3 women experience urinary incontinence. This tends to be about 2/3 of the patients are 50-, 60-year-old women.

This is another competitive landscape chart. And what it shows you is there's a lot of companies that have come and gone through here. You can see Bayer, Shionogi, GSK, Merck, a lot of people have had programs here, again, back to peripheral only agents. So what's left in this space, GSK bought Bellus for any of you that followed that company a couple of years ago for $2 billion. They'll read out their Phase III data this quarter, third quarter of this year. We'll watch for that. I think they've had to migrate their program to only focusing on the most severe coughers. So we think that we can have sort of a better option for patients here.

And there's another small company Nocion, which will read out later this year as well with an inhaled therapy. So not a lot of competition here. We ran a IIa crossover study. This was about 60 patients, same primary endpoint, the subjective measurement of cough, similar secondary end points to what you saw, 21-day study.

And just to summarize the data, you can see the upper left. There was a very big treatment effect in this condition, 65% reduction in cough after 3 weeks for these patients. That resulted in about a 56% treatment effect. The second best set of data, which I know you can't cross compare across trials. But in a trial that had been optimized by Bellus, they had a 34% placebo-adjusted change. So we've had much better data that's been shown to date.

The bottom left answered an important question here because both Merck and GSK's program have had to migrate towards only looking at the most severe coughers. I think it's because they only affect cough being triggered through the P2X3 receptors. They're not touching anything else. So in the cough that they catch, they need to have a big effect. Because of our central mechanism, we had a hypothesis that it wouldn't matter for us what baseline cough counts here were. So we stratified across people with 10 to 19 coughs an hour and greater than 20. And what you can see here, if you focus on the blue bar, the drug arm is it didn't matter what baseline cough counts were. This enabled us actually in our FDA discussions to have FDA encourage us to really open this up across cough counts. They don't want us focused on moderate and severe. People have an issue with coughers, they want them to be able to get our drug.

The upper right is the responder analysis, again, big effect. And the bottom right is an interesting chart and sort of the jumping off point for our next study, which is this was a titration study. So people started at 27 went to 54, made their way up by the week 3 to 108. And what you can see here is we put a cough monitor on people after week 1, that whole effect was there at the lowest dose at week 1. So sort of in summary, big effect that worked in almost everyone across cough counts and seems to work very rapidly at low doses.

So as we move forward, Adverse events, by the way, look the same. You see kind of the similar cast of characters here on the left. And the bottom right chart sort of shows you what I mentioned before, which is most of these AEs happen in week 1 and then mitigate themselves over time. So this is all about getting the titration schedule, right. So as we move forward, the question we need to answer in our IIb study is what is the minimally effective dose here. I think from that crossover trial, I'm not sure we know that. Remember in IPF, our dose was 54 milligrams BID. I just showed you in refractory chronic cough. It looks like the whole effect is there at 27 milligrams. So we're going back, we're going to run sort of a proper dose ranging study. We'll look at 54 milligrams BID, 27 milligrams BID, and we're actually looking at 27 milligrams QD to be given at night, most of this cough kicks off in the morning to see if we can impact it with a much lower dose. So this study is starting this quarter, and we'll also read out later in '27, which I'll show you.

So really kind of similar endpoints we already talked about. This is powered at 90% power, and we're excited to sort of see this next round of data.

So to wrap this up, our milestone chart, you can see we're kicking off both the refractory chronic cough and first IPF study this quarter. Then we'll start the second IPF cough-related trial in the non-IPF ILD IIb portion. We're actually doing one protocol that will roll into a Phase III, assuming that goes well, and what you can see here is this essentially results in a whole lot of data reading out in the second half of '27, the final IPF trial reading out in the first half of '28. If both of those are positive, we're planning for a second half of '28 submission. So we're sort of eyeing that down. We do have -- we have about $172 million at the end of the first quarter. We just did a nice offering here 2 weeks ago. So we have a little over $300 million on the balance sheet. That takes us through 2030. So that should get us through an approval on IPF. It gets us through our remaining development work on non-IPF ILD, and it will get us through this study in RCC. What we have not funded here is a Phase III in RCC or any of the commercial work, we can sort that out later.

So we feel like we're in good shape. We're in a space that has a big unmet medical need for patients, there's virtually very little competition left. We have the cash to execute against all these development milestones, and we'll not need to raise money off the back of all these. So the company is well positioned. So that's Trevi.

I will now take questions from the audience. Thank you for coming.

Welcome in New York, and we also have a lot of people online joining for the webcast. So appreciate your support and interest.

Our team is really excited to share more color on our path forward. A lot of you in this room see me all the time, and I always say people get bored of my voice. So I'm really happy to have you meet some of the depth in the company and around the field.

I think you're going to feel the energy of our group and the opportunity today as we work to move this drug closer to patients.

So I just -- I should reference our safe harbor. I shouldn't skip over that because we are going to be talking a lot about the future. So obviously, look at the risks around the company.

So I want to take a minute and introduce you to our leadership team. As you guys know, it takes a lot of people to execute against this plan we're on. So first, our full C-suite team is here. I'm sure you've all met most of them. I know I told you not to stand up, but I want you to stand up. I'm joined by Jim Cassella, our Chief Development Officer; Dave Hastings, our Chief Financial Officer; and Farrell Simon, our Chief Commercial Officer. They will all join me in presenting today.

We're also joined by our scientific Co-Founder, Tom [indiscernible] standup, Dr. Thomas Sciascia, Tom and I started this company more than 10 years ago together based on really his ideas and his lens as a neurologist. So he's the brains behind the operation. We've been a great team. We've worked together 20 years. And I just want to recognize his huge scientific contribution not only to Trevi, but to the field, Tom. So thank you for being here.

Finally, we also have several of our company leaders in the room who are the boots on the ground, executing the strategy to stand up. I'm not going to introduce every one of you, but definitely takes an army to get this done. We're 40 people strong and really appreciate you guys coming. So thank you.

Today, we're also joined by two of the top KOLs in our space, and we're very lucky to get some of their time. They're super busy. [ Dr. Toby Maher ], will join us by Zoom because he's actually in clinic today on the West Coast. And we're super fortunate to have [ Dr. Peter Dispan ] and guides, who will join us in person and be here through lunch as well. I'll introduce more of their distinguished backgrounds when we get to each of their sections.

We have a full morning so I'm going to keep moving. And with the exception of [ Dr. Maher's and Peter's ] section, the two KOLs, we're hoping you can hold questions until the end. We've left 20 minutes, and you can question the management team.

Starting today, we are kicking off a patient testimonial campaign, raising awareness around what it's like to live with chronic cough. So you are the first group, you get a preview -- sneak preview of a couple of our videos, which will run over the next couple of months. So let's start with the north star in our industry. I know that's what we all focus on the patient.

[Presentation]

It's powerful and credit to [ Katy ]. She's been -- she has a patient advisory panel, which we circle back too often, and it's very helpful as toys be focused on their needs.

I want to show you on one slide, our strategy to build a leadership position in chronic cough. There's a high unmet need here. And we believe if we are successful, not only can we provide hope and therapy for these patients but we can also create significant shareholder value. There's many of you in this room. I've met several shareholders that bought the stock at $0.50 to $1. That was when we had a lot of binary risk in front of us. We fortunately made our way our journey through a lot of those moments. And now it really is about executing a Phase III program and getting to the market. So we're excited about that path forward.

I'm going to take you through the [ build-it-up ] vision. This sort of build that I show you, my team is going to help go through each of those pillars in more detail today.

So first of all, it all starts with the drug, Haduvio, now [ nalbuphine ]. What's unique about our drug, we believe it has got this dual mechanism of action. It targets not only the central part of the brain, but the peripheral part of the lung. And Jim is going to actually take you through a nice schematic of why that's important, but it works along the whole cough reflex arc.

We have three pillars for growth. One of the challenges we've had is this drug has worked in everything we've looked at it in. So we wanted to really focus on the most severe cough conditions, we're a small company and drive those over the finish line. So we've always been IPF cost led in the company. We have strong Phase II data, we had a very constructive end of Phase II meeting. FDA was interested in what we were doing, gave us clear direction. Jim and his team have a clear playbook of how to get this to the FDA, what we need to do. And we're initiating our Phase III program this quarter.

We're adding on to that, the non-IPF ILD portion. We believe we have proof of concept in this indication through our IPF work. And I've asked Dr. Maher today to talk to you about why he believes IPF and ILD are the same patient from our perspective.

We are looking to initiate a Phase IIb/III program later this year after meeting with the FDA. And refractory chronic cough for RCC, we believe we have best-in-class Phase IIa data for those of you many in the room followed [ Bellas ], which was acquired by GSK. They do have their data coming in the third quarter. There's plenty of room for both of us here. There's a lot of patients with a lot of unmet need. So I don't think it changes at all what we're doing.

These are very large available markets. And for all the analysts in the room who have had to model this, these numbers can get very big very quickly. IPF, we estimate it's about a $5 billion to $12 billion market. And Farrell is going to show you a lot of color on this today. No approved therapies, no competition left. There's been drugs tried here, they've all failed. The antifibrotics don't move the needle on cough. Non-IPF ILD, that's a $7 billion to $15 billion marketplace, no approved therapies, no competition. And refractory chronic cough is a very big market, $20-plus billion, no FDA-approved therapies, and I mentioned one other data point coming.

We've been very intentional about targeting areas that we can drive to the market ourselves. I did not want to be beholden to big pharma deciding they're going to take you out. Look, as I say to everyone, they show up with a big enough check. We're a publicly traded company. So obviously, we'll look at it. But I think that there's been lots of companies who have shown us you can do respiratory launches very well on your own, and we are scaling the company to do that. So we will be prepared for that moment to take this to market ourselves.

Specialty pricing in this area. Again, Farrell share some of that work. Specialty size sales force, 50 to 75 reps. And this commercialization is very executable. Think [ Verona ], think [ Insmed ]. They've got the playbook here. They did an excellent job at it. And we believe not only can this get a drug to the patients you just saw whose life we think we can impact dramatically, but we can also create a lot of shareholder value along the way. And I think you guys have seen, as we've reported out our data -- this has just been a nice build in the story.

So with that, I'm going to turn it over to our Chief Development Officer and my good friend, Jim. Jim has been around the company a long time. And just quickly on Jim's background, Jim is a PhD neuroscientist, and he's been working in neuro area for, let's say, 30-plus years, might even be another decade than that. But because of that, he brings a lot of tricks of the trade, I think of dealing drugs or dealing with drugs going to the CNS. So we're super happy to have him.

Good morning, everybody. Thank you. Great to be here, and thank you all for coming. It's way too early in the morning to be talking about neuro stuff, but some people say never the right time of day to talk about neuro stuff. But I just want to touch a little bit on a few things today. it's probably a little different than some of you you've seen me before, where I talk more about clinical data. This is probably going to be a little bit more eclectic I want to talk a little bit about some fundamentals that underlie our program. Talk a little bit about some insights we've learned along the way and then give you an update on sort of where we are with the program.

So first of all, I want to touch on why nalbuphine seems to be the right choice for drug to treat chronic cough. And for that, I think we have to go back to sort of the anatomy of the cough. As Tom Sciascia says, you can't have cough without a brain, right? I mean cough is in the early mediated mechanism. So as we look at what's going on here, we know that you stimulate are entering the lung they activate sensory neuro fibers. There are ion channels and receptors involved on the [ vagus sensory ] nerves that send signals up to the brain. Brainstem coordinates motor responses for cough. We have motor neurons triggering respiratory muscles to sort of provoke the coughing, reflex. And then we have higher brain centers that are obviously involved in sort of the processing of the urge the cough, the initiation of the cost intensity, whether you're going to suppress the cough or reaching even activate the cough.

But what we do know is that dysregulation of any of these pathways can lead to this concept of cough hypersensitivity. And we're going to shortcut a lot of these different big picture stories here to really get down to some of the essence. And I think -- it's fair to say that cough hypersensitivity is really the underlying concept here for chronic cough. And it just leads to exaggerated responses.

This is mediated by both central and peripheral mechanisms. When we're looking at peripheral what we're talking about, again, neural, we're talking about sensory fibers that become a little bit more excitable. This could be because of local tissue damage as you may have with a case of patients with IPF or mechanical stress as a result of chronic cough that may be resulting from a bout of asthma or something like that or just loss of lung tissue. But the idea here on this whole chronic hypersensitization phenomena is that you have triggering stimuli more likely to produce a cough response than you had before. In fact, some things that may have never produce a cough response now can elicit that cough.

So the system is designed so that you have a direct pathway to the brain. We're not going to take the time to go through spinal cord. So the biggest nerve ends up being a very, very important part of the signaling pathway here. We have a direct pathway going right to the brainstem through the [ vagus ]. These things are now being amplified peripherally being sent along to the brain.

And then in the central sensitization part of this story, we have things that are being amplified, whether excitatory centers that are being jazzed up or whether it's inhibitory centers that are being turned off, that's kind of phenomena with the overall result of being hypersensitized so more likely to elicit this cough.

So that's sort of a little bit on the sort of the brief overview of the anatomy. But when we talk about the pharmacology related to oh, there's lots of different things that you could be looking at. Of course, we're going to be talking about the opioids. The opioids have -- happen to be in the right place and sort of at the right time. So when we talk about the opioid receptors both in this peripheral and central nervous system schema, really talking about the opioids primarily [ CAPA MU ]. And when we look at the periphery part of it, we're really talking about a phenomenon like activation of opioid receptors in the lung, can have inhibitory effects on this pathway going to the brain. When we talk about the central mechanism here, we're really talking about these opioid receptors, primarily [ CAPA ] receptors being in the right place. And when we're talking about this concept of sensitization. These are clearly in the right areas of the brain that underlie or mediate the sensitization phenomenon.

We're not just talking about cough, talking about pain and wind up and we're talking about itch and things like that. So there is this concept of sensitization, this amplification process that is really occurring at both the peripheral and central nervous system level. And the [ CAPA ] receptors are really key here. So when we think about nalbuphine and we think about our drug, let's think about it in concept of that, think of the opioid receptor system and we think about our [ CAPA ] agonism, that's probably more related to what we're seeing here on the efficacy side. And there's very good reason to believe that this is the phenomenon related to the basic anatomy in pharmacology, what's going on here with sensitization.

But as we think about opioids and we think about sort of the downside, the side effect side of opioids, we know that there's concerns about opioids, it's out there. And when we think about this and we think about primarily the [ CAPA ] and immune receptors here.

Nalbuphine is a class of drug. This is a drug that's over 50 years old. This drug and the class that it's in was really designed to be unique when we think about opioids. Not all opioids are the same. There are different levels of intrinsic activity. They can have agonist activity that can have antagonist activity. But we do want to highlight that nalbuphine being part of this agonist and mixed agonist class that it's in really does have sort of a yin-and-yang effect. We talk about [ CAPA ] being important maybe for the cough response, but the new antagonism here is really important for the parts that people get concerned about when you talk about opioids.

So the [ CAPA ] agonist and the mu agonist class was really designed to mitigate abuse potential and minimize risk of respiratory depression, euphoria abuse that are clearly associated with drugs like fentanyl and those fuller agonist drugs. And in the U.S., this nalbuphine was approved in 1979. It's used to treat moderate to severe pain, and it's used during labor and delivery, which says something about the drug and its perceived safety. And it's been not controlled in the U.S. for a very, very long period of time, decades, and I think that does reflect on its low abuse potential.

When we think about the classes of medications that are in the opioid class, we immediately think of drugs like fentanyl and morphine, hydromorphone, which are full agonists. These are agonist at the [ MU ] receptor they represent one end of the spectrum here. When we go to the other end of the spectrum, we think of drugs like naloxone, naltrexone these are the opioid antagonist, these drugs are actually used to antagonize some of the adverse events that you see with the drugs like fentanyl. We all know that you can now get naloxone in drugstores and you can give it to anybody who is suspected of having an overdose. So it's that available. It reverses the effects.

But when you look across the spectrum now of opioid activity, we have other drugs like butorphanol, which are more like partial agonists mean they have some cap agonist activity they're not quite as potent, let's say, as the drugs on the left, the full [ MU ] agonist and we get to nalbuphine. Nalbuphine down towards the naloxone -- they actually have a chemical similarity here. And what we're looking at is our CAPA agonism, our [ MU ] antagonism, which really provides some unique perspectives on the drug and some [indiscernible] activity which is much more like naloxone.

When we think about naloxone, we think naloxone able to reverse respiratory depression, which is what we all know and see in the news, then that is a characteristic of this antagonistic class. We also have data that says that nalbuphine because of this immune antagonism can reverse respiratory depression. That's been shown in people has been shown in animals. So very, very similarity there.

We also think about opioid withdrawal. We know that naloxone in drugs like naltrexone can precipitate opioid withdrawal and people who are abusing opioids. Well, we get the same thing with nalbuphine right? We know that nalbuphine used in chronic users can precipitate withdrawal. So when we think about this in terms of a spectrum and in terms of activity, not all opioids are the same. We have these full agonists here full bore, high potency. We have the antagonist. We have [ CAPA ] agonist activities in nalbuphine but on the safety side, it behaves much more like a naloxone. So I think that's just something to keep in mind, not all opioids are the same.

We see that actually reflected in scheduling as well. We know that these are highly scheduled compounds because they have higher abuse potential. We go to naloxone. We have no scheduling there, very low abuse potential, and we've seen that nalbuphine has not been scheduled in the U.S. for decades. So again, on the spectrum of scheduling and abuse potential, it's always been on that side of the story.

So a little bit of perspective on why opioids are important for cough, Why nalbuphine is really important in the context of its efficacy in terms of [ CAPA ] and its safety in terms of the new antagonism.

So I said it was going to be a little eclectic, so we're going to switch a little bit now to our programs and really talk about our -- what's coming up and how things are shaping up. But before we get there, I have to say if there's anything you want to take home today is going to be our study names.

So there's been a lot of work that has gone on here. We get thank [ Katy ] and her team for really -- now our IPF program is going to be Ocean. We're going to talk about Ocean 1 and Ocean 2 today, and our RCC is going to be late. And you have to agree that these are beautiful logos here. So again, take them home, we'll give out pamphlet at some point.

Let's talk about the actual framework of our trial. So in the Ocean program for IPF, we're going to be running two trials. We talked about this in the past. We had a great end of Phase II meeting to talk about with the FDA. This is a general framework that I wanted to put in context for you. Ocean 1 is going to be our longer trial. We always have a 2-week titration period. We'll be ramping up from 27 once a day to twice a day during that titration period. This is true now across the ocean program. We have 52 weeks of fixed-dose dosing in our Ocean 1, followed by a 3-week safety follow-up to where we're going to look at what happens when the subjects -- the patients are off drug, but we're looking at withdrawal symptoms and things like that, that are going to be very, very important the FDA and from a regulated perspective.

Ocean 2, as we mentioned before, is going to be a shorter trial. We're going to be looking at around 200 patients here. Same dynamics here. Only the fixed-dose portion of the trial will be 12 weeks on fixed dose. The whole safety follow-up is going to be the same as we talk about that throughout all the programs.

When we think about this in terms of time frame, as Jen mentioned, we'll be talking about our OCEAN 1 trial kicking off this quarter. We'll follow it up in 3Q with Ocean 2. We're looking at data readouts then in the second half of '27 and the first half of '28, we're going to talk about this in terms of halves, Don't read into where the diamonds are on the plan. Those are not exact.

When we think about powering and how we're really prepared to go into our pivotal program for the primary efficacy endpoints for both Ocean 1 and Ocean 2, we're looking at greater than 90% power for both the primary efficacy and the key secondary end points. We're looking at the 54-milligram twice a day dosing. It's a 2:1 randomization, as you saw previously, we powered this based on a 30% delta between placebo and active based on our CORAL study. When we look at Ocean 1, we'll probably be about 80 to 90 sites in the U.S., Canada, Spain, Poland and the U.K. 60% to 70% of those sites will be in the U.S. or subjects enrolled will be in the U.S. and Ocean 2, about 70, 80 sites, trim back a little bit U.S., Canada and U.K.

The primary [ effect ] standpoint is the same as what we studied so far. It was driven us so far to this date where we're looking at the objective of count, 24-hour cough count. The primary efficacy end point will be after 24 weeks of fixed dose in Ocean 1, 12 weeks of fixed dosing Ocean 2.

And then when we look at the key secondary endpoints, here's our hierarchy. We're focusing on [ CSNRS ], which is cost severity to some cuts of the efficacy data with cough monitor cough frequency, patient reported breathless, et cetera. So these are all things that have been discussed with the FDA.

Turning to our Lake program, our RCC program. Again, you see the same kind of framework here in what we're looking at for now. This is our first parallel arm study looking in patients with refractory kind of cough. We have a screening period, that will include a placebo run-in. We have 4 doses in this -- or 3 active doses than placebo in here, where we're looking at 27 once a day, 27 BID and 54 BID. The purpose of this trial, if we recall, our RIVER data, we never established a minimally effective dose going at 27 BID. So we actually are cutting the dose down to once a day dosing at 27. It's a parallel arm study. We're going to learn a lot of information from this because we know that parallel arm could give you a little bit more range of responses between active and placebo versus the RIVER study, which was a crossover design. And then as typical, you're going to see we have a 3-week safety follow-up period.

When we look at the details of this, as Jen said, we're going to be starting this trial this quarter. With 4 weeks of fixed dosing, we'll have readouts in the second half of '27. And what we are aiming for is the SSR sample size reestimation to just gauge the size of the study that we went in with, with about -- with an [ add of 100 ] and make sure like we do with CORAL that if we are going to look at our conditional powering, if it looks like it's right, we stay with the same and if it looks like we need to bump it up a little bit, we will bump it up proportionately.

We're, again, designed to be 90% power or 4 doses, 1-to-1 randomization for 27 QD BID, 54 BID and placebo, based on the river result and our data coming in from our IPF trials were effect sizes based on a 30% delta between active and placebo for the 54 dose and looking at 40 sites in U.K., Canada and Poland, same primary endpoints as we've done with the objective cough count using [ Vitalojak ]. I'll talk a little bit about that in a second. And our primary endpoints in terms of patient reported outcome, looking at our essentials of cost frequency, cost severity. We're looking at quality of life related to cough. And we are incorporating a urinary incontinence scale in here too because we know that, that is the complaints that we see with patients with refractory chronic cough.

We have talked about our non-IPF ILD program. This is something that's going to be coming up. But when we look at the fundamentals of the design, it's very much like what you've seen. We do have a pattern here because it's a pattern that works. This is something that the FDA has agreed to with our IPF program. So with screening period, titration will be 2 weeks, fixed dose period. This is going to be an adaptive design. I'll describe that in a second. But the Phase IIb portion of this is going to be looking at the dose ranging exactly as we did with CORAL. It is a slightly different population. This is non-IPF versus the IPF population from CORAL. We will look at the same dose range to confirm our dose going into the Phase III program, just like CORAL will be a 4-week assessment here, a fixed dose and then safety follow-up.

The Phase III will be is a little [ TBD ] at this point in time. We know what the FDA wants us to do for IPF. We will follow -- we'll pull all of that into the program. But some of the numbers need to be determined here based on the outcome from the Phase IIb trial. But we're anticipating same kind of thing with the safety lead-in period, a titration period, 52 weeks of fixed dosing and then our safety follow-up.

In terms of these details here, we will have a discussion with the FDA in Q3 to really lay out the plan that we have going forward. This would be an [ sNDA ] approach, a fast following. Once we have the approval for the IPF program. 4 weeks of fixed dosing for the IIb trial roughly ends of 100 to 120 interim readout that will really help us gauge what we need to do for the Phase III portion of this. This is an adaptive design, single protocol. That's what we'll be submitting and having that discussion with the FDA. So the scope of our program and the exact specifics with the full protocol submitted for that Type C meeting.

We have a lot of the same assumptions coming into this program that we had for the IPF program. We will do about 60 centers in the U.S., Canada and the U.K. to do this Phase IIb portion of it. The Phase III will follow very similarly to what we did with IPF to amortization just helps keep higher numbers of patients on drug and then exactly what we're doing here for the IPF program.

So again, just a snapshot of what we're doing there, lots of activities going on, lots of good movement. All those things are in play and moving along very nicely.

In terms of some insights here, I said we're going to be a little bit of collective here, but we haven't gone back and looked at a lot of our data. While some people ask us, are you doing like you've got to get Phase III going. Like there's a lot of analyses that we've done along the way to really help inform us on the kinds of things that we need to do here.

I wanted to touch base on this a little bit because adverse events, we know this is an opioid class drug. There are known characteristics of adverse events. We're going to talk about what they are and what we learned about them along the way.

So what's absolutely remarkable about this drug in his 50-plus-year history, that it has a very common pattern of adverse events. We know this not only from this program, but we've seen it in the programs that we had previously when we were in the dermatology space and in the pain space. But when we look at what we saw in our RIVER trial for an RCC, looking at the rank ordering of the common adverse events, I'm not talking about severity, but this is just in terms of occurrence, constipation, [indiscernible], insomnia, headache, dizziness, fatigue, very common to this class of drug, very common to nalbuphine. When we look at the IPF population in the CORAL study, again, this IIb study, nausea, vomiting, constipation, dizziness or headache fatigue sales, rank ordering, they're almost identical. Again, across very different populations. We see a very what we would call well-behaved adverse event profile.

But what we've known about this drug and what I'm trying to show you here with some real numbers is really shown on the right-hand side is that when it comes to these adverse events, they come on early and they're not necessarily dose related.

So when we look at our the occurrence by day and summed up over weeks, we see that most of the adverse events. Now this is from our RIVER trial, the crossover study, most of the adverse events that are occurring here that are GI or CNS in nature are really occurring with the first 7 days of dosing. Keep in mind that over that first 7 days, we're really looking at '27 BID, then you see things really fall off over the higher doses over a longer time, which is really characterized here. So what we're finding here, and we've seen this -- we have similar data, I don't have it to show you today, but we have similar data that is from our IPF trial as well. The adverse events come on early, they come on with initiation of dosing and they usually are occurring at the lowest dose. So not dose-related.

This has led us to really incorporate the strategy into our future trials. You're seeing this in our Phase III program, where in Lake and Ocean will start off with QD dosing at night, helps mitigate some of the common side effects that you see, especially the CNS ones. We'll do that for a week, hoping that we can really help mitigate and get down some of these adverse events that are being reported because a lot of these things will be occurring while they're sleeping.

The other important part of it when we talk to patients, not only in our clinical trials, but when you start thinking about this in the commercial marketplace, you're going to have these adverse events that are going to come on early, just hang with it. They're going to -- we can mitigate this to the extent we can. But when they come on, they're transient. So how often do they -- how long do they last? And when you look at the most common adverse events that we have in our program from constipation to headache to dizziness. When we look at the median here, the means, again, first look here, most of these, I want to say, about 75% of these adverse events that we see are mild in nature. So that's very characteristic of what we see. But what we also see is that, for the most part, some of these are lasting a couple of days like headache, dizziness, vomiting, even short term. And then when we look at some of the things that may last a little bit longer, maybe some of the constipation and some of the semblance.

But on average [ meetings or means ], these are still in a relatively short period of time when you start initiating these doses. So I think this is something that we're bringing forward, finding more ways to mitigate the common adverse events that you see with this class of drug. And this will really help us try to mitigate some of these things for keeping patients engaged in our trials.

So I want to turn to the way that we measure cough. The objective cough count is done with a device called by [ Vitalojak ], it's from a company called [ Vitalograph ]. This goes back. We get a lot of questions on [ Merck ] in the early days with RCC, and there was questions about whether or not there was issues with cough counting.

And [ Merck ] was -- they sort of -- they were first and they had the bleeding edge of trying to get something introduced for cough. And one of the things that was learned during that whole process was that the FDA wanted this cough to be through a validated system. They use exactly the same system that we use. So it's the [ Vitalojak ]. The program that GSK is running with the [ Bellas ] drug is also using the same system.

So what's going on, basically, this system is designed to pick up cough sounds. It's got a 510(k) approval for that. It's got a CE Mark. It does pick up cough sounds. It's reliable for picking up these cough sounds. But the issue comes with cough counting. This is a 24-hour cough count. And these are scored manually by people. So there's a compression algorithm that is used, and I think there was the basis of some of the concerns they had with the initial [ Merck ] filing is that you have to show that the way that you can press the data from a 24-hour recording because it's manually scored down to something that's more manageable in something in the 3- to 4-hour time period that's a validated system. You're not losing things along the way. And all the algorithm is doing is taking out sounds where there's no sound -- taking out periods where there's no sound.

So the essence of this is do you have a validated way for compressing the data down so that the accounting can be done. And I have to say that across all the programs and the FDA considers that manual accounting with actual raters is the gold standard for doing this.

So we, like others, have had to then take a look at validating our cough counting. And so there was a validation study that we've talked about in the past. This is really all about the compression algorithm that they use with this recording system, which all came out of the learnings and from the trials and errors of the [ Merck ] filing.

So just to make it clear, there's been a lot of learnings from there. We've done all the work. This is really required by the FDA for all the companies that are working with this, and [ Vitalojak ] is really the industry standard for doing this.

So the nature of the validation study really was to look at two things. It was the agreement between the total of counts in this 24-hour recording session, which is the raw data when it's compressed down to this 4-hour cough session, which is the compressed data of course, because these are human raters, you're always required to look at inter-rater reliability. So how tight is the relationship when one person is doing the accounting versus somebody else doing the accounting. So that's the nature of the validation work that we've been doing.

Happy to say that we completed this work for the CORAL study. This was an important part of what we do post study. So this is done on the data from the CORAL study, but again, not looking for drug effect, we're looking for the relationship between the press and the uncompressed cough counts, and we're looking for the relationship between the raters.

Very, very top line data, a lot of things for you to consider here. I want you to focus on just two things here. When you look at the relationship, the agreement between uncompressed and compressed cough recordings, this agreement study you look at the plus or minus 10% here represented by this purple band, we're dabs back in the middle. So this is looking at the relationship of compressed and uncompressed over time, looking at different scores. We're within 2% or 3%. This is highly reliable across this range from 200 to 2,000 cough counts.

So this is one thing that shows that we have very high reliability in the compression algorithm that they use and we'll be sending this into the FDA to convince them that our CORAL study had very high relationship between the uncompressed and the compressed showing that our cough counting was valid.

And then the other thing on the inner reliability, there were three raters in this validation study. So these are just showing you the relationship that, again, with our purple being our bands of acceptance, our acceptance threshold, this is right 0 and then a couple of percentage points around the 0 line over a range of cough counts between raters 1 and 2, 2 and 3, 1 and 3, so very highly reliable cough counting. These are data that will support our important CORAL study. With any luck, we don't have to do this for our Phase III program because these data are so tight and we had an agreement with the FDA that if these look good, we can talk to them about not having to do this for the Phase III in the IPF population. These data are very strong. We'll be submitting this report to them. So this is the first glimpse that says we have high accountability between compressed and uncompressed cough counts and high reliability in the readers that were there to do it.

And then, of course, we had our end of Phase II meeting. I don't want to spend any more time talking about the clinical portion, which we really spent a lot of time on. But I'm not sure many of you know that we actually had two in the Phase II meetings. We always have a chemistry manufacturing control a CMC meeting as well. So we submitted a bunch of questions regarding our API, about release specifications, really in-the-weeds kind of stuff, but really important because we all know that complete response letters, a lot of the time are related to your chemistry. So we really took a head-on approach to making sure that the FDA understands where we are with our chemistry with our API and with our drug product. And that they're in agreement that when it comes time for NDA filing that we know what we're doing and we know what we need to give them. So that's really the nature of this discussion at the end of Phase II meeting for the CMC part.

We talked about the acceptability of the excipients in our product, our proposed specification and test for doing it for key things like safety and potency and purity and our approach to registration stability we got really strong and informative responses in a written response back from the FDA so much so that we didn't even have to have the meeting. So we had a clinical meeting, but for the CMC and the Phase II meeting, we definitely got the responses that we needed to move forward. So we're feeling very comfortable about that as we look at our chemistry and the actual product that patients are going to be taken, which we know is a very important part of the NDA process.

And finally, I just wanted to touch on the fact that we had a lot of solid data that we've generated in our program. We're having a very big presence at the ATI meeting coming up in a few weeks now. And some of the things that we just wanted to highlight for you is that we have a great presentation by [ Dr. Phil Malone ], who will be also -- who will be describing what we have our CORAL data, but we also have some interesting primary sub-analyses that will be given an oral presentation on Monday.

We have a number of other presentations that are in poster format with [ Dr. Jackie Smith ], who really helped us analyze not only our cough counting, but also cough bots because people caught in bout and it's another very interesting parameter that everyone is interested in, especially the FDA. So we started digging in on cough bout. So we'll be presenting some cough out data from our CORAL study, but we'll also be presenting some cough bout data from our RIVER study. So there's some very interesting things that we found there. As we talked about previously, we have some very interesting findings on breathless is from our CORAL study and [ Dr. Don Mahler ], who's an expert in this space will really be presenting that poster for us. We've done a DDI work with nalbuphine and [ terfenadine ]. We'll be presenting the data there. I'll be handling that poster where we found that there's really no effects in giving a mutual PK effects on [ terfenadine ] or tentative with our drug. And of course, there have been some nice work on evaluating the sort of emotional and social well-being in patients, and this will be given by [ Sogaris ], who will be really giving a poster on Monday.

So a lot of presence there, some new and interesting data that's going to be presented there, really looking forward. If you're down there, please stop by and see us. And turn it over to Jen.

Thank you I was high speed. Do we have Toby online? Yes, I'm getting the thumbs up. Toby. Sorry, we're running a little late. I'm going to introduce you to [ Dr. Toby Maher ], if you ever saw his real CV, it's super impressive. Can you go back because I do want to read his credentials, oh, that's me, I guess.

Toby is a professor of Medicine and Director of an ILD Clinic at the [ Keck ] School of Medicine at USC, you can see as division of pulmonary critical care and sleep medicine. We actually met him in the U.K. at the Royal [ Brompton ] and just add some personal flavor. Toby's clinic was actually the first clinic to dose a cough patient for us in 2018. He's been a key adviser to Trevi along the way. He's reviewed our protocols. He's going to be in our Ocean study, our big one, and he went to the FDA with us. He's a very strong voice, not only in cough, more importantly, in a lot of the IPF ILD work that's going on. He presented all of [ BI's Jaca ] data. So he is a big name. He's in the clinic today. We're super appreciative that we have him joining us.

And we basically asked him to spend a little bit of time talking about IPF ILD, the differences of similarities about cough, sharing his perspective on [ antifibrotics ]. Many of you are investors in those companies, the changing landscape. And hopefully, at the end, if Toby has got 5 minutes, we'll ask questions from the audience because we will lose him. So do you guys have things you want to ask him, go ahead. So go ahead and bring up Toby.

Toby, thank you. We really appreciate you joining us, and I'll turn the mic over to you.

Great. Thank you. I'm pleasure to be able to join you all virtually. As you said, I've got clinic today, which is why I'm wearing a suit and tie. I'm not doing this for you. I apologize.

So yes, as you introduced me, thank you for the kind words. I first met Trevi, as you've said, 8, 9 years ago now. So it's been a journey. It's been quite exciting. It's been an important journey. I was in London, as you said, but have now transitioned to the U.S. So I've got experience of the trials and tribulations of trying to treat cough in two very different countries or two countries were very different approaches to symptom management and morphine-based or opioid-based treatment. So that's been interesting.

But anyway, you've asked me to talk today about the IPF and ILD treatment landscape and the importance of cough across these ranges of diseases. I suspect IPF is very familiar to everyone. It is a progressive disease characterized by scarring of the lungs with an average untreated survival of about 3 to 4 years. We've obviously seen some developments in the treatment of the underlying disease. We now have our three [ antifibrotics ] and with the recent [ Tyvaso ] data, I think we're anticipating a fourth in the near future.

I think one of the big challenges we've had with the [ antifibrotic ] drugs is that although they slow disease progression and almost certainly do extend lifespan for patients. They don't have a meaningful impact on symptoms. And so we still have the challenge that when our patients come to clinic, they're reporting a massive impact of their disease on their quality of life both through breathlessness, but also importantly, for a significant proportion of cough, and there has been little that we've been able to do about it with our existing antifibrotic drugs. And that remains as true now as it did a decade ago.

And I think as has probably been said many times now in these meetings, cough is something we don't think about, except on the very few occasions that were unlucky enough to get a respiratory tract infection and experience cost for ourselves. But for patients living with IPF who cough every day, it is a socially and physically disabling symptom. Cough is -- if you imagine, sitting on a plane or in a restaurant or in a theater. Having people coughing around you is deeply annoying. And so the unfortunate individual who is doing the coughing is generally aware that what they're doing is considered deeply antisocial. It leads to patients with pulmonary fibrosis withdrawing into themselves, reducing their social life, not going to restaurants with friends and family not going to theaters, avoiding travel because they don't want the discussed looks from fellow travelers as they sit their coughing in their airplane seat.

Also, IPF is a disease of older adults. So frequently, they have things like stress urinary incontinence and coughing will almost certainly make that worse. So it's sort of one of the unspoken consequences of coughing is that it will often exacerbate things like stress incontinence. So it really is a very important symptom that can be incredibly debilitating for patients. And until now, there's really been nothing that we can do for it.

Clinicians like to be inventive. So in clinical practice, we use things like inhaled bronchodilators, we even use low doses of corticosteroids. But we know that those drugs don't really work beyond having a placebo effect. And so there is a huge unmet need for effective therapies that moderate cough in patients with pulmonary fibrosis.

And I think as we look to the future, it is worth digging into United Therapeutics data with [ treprostinil ]. We know that in how [ treprostinil ] is a drug that causes cough. It causes cough in patients with primary or pulmonary arterial hypertension. So individuals who don't have intrinsic lung disease. And we can see from the dropout rates in the TETON trials that cough was a significant issue for patients in those studies. The dropout rate, as reported in the press release, for TETON 1 was approaching 40%, and I strongly suspect most of that was cough driven.

And so we are shortly going to be in a situation where one of our approved drugs exacerbates the -- one of the key underlying symptoms of the disease. And I think if we are going to be able to leverage the beneficial effects of a drug like Tyvaso on both fibrosis and pulmonary hypertension, it is going to be incredibly important that we can also effectively manage the cost in these patients. So I think cough's already an important issue, and it's going to become increasingly so when we have an effective antifibrotic and [ PH ] drug that causes coughs one of its side effects.

And then just to pivot and talk about interstitial lung disease in general. I think one of the things that we've -- we, as experts dealing with institutional lung disease have made life difficult for ourselves by developing a nomenclature that is both repetitive and highly technical. And so we often talk about interstitial lung disease. We talk about pulmonary fibrosis. We talk about parenchymal lung disease. We talk about inflammatory lung diseases, all of these things are, to a certain extent, synonymous. So when we talk about interstitial lung disease, we're talking about any one of about 200 disorders that affect the wall of the Alveolus. So the area in the long way gas exchange takes place.

And interstitial lung diseases are characterized by either scarring or inflammation of the Alveola wall and idiopathic [ comer ] fibrosis is both the most common of those disorders but also the one that tends to be most aggressive, which is to say, gets worse, most rapidly.

And so 20 years ago, when we thought about developing antifibrotic therapy, there was a key focus on idiopathic pulmonary fibrosis because that was the disease where we could see the biggest change occurring over time. So it was the disease in which it was most feasible to test potential antifibrotic drugs. It was also the most common of the individual -- of the many diseases that make up interstitial lung disease, and therefore, it made sense to focus on idiopathic pulmonary fibrosis for those two reasons.

But in doing that, we excluded the other 199 interstitial lung diseases. The vast majority of which behave in a manner that is very similar to idiopathic pulmonary fibrosis, as we've increasingly come to see the majority of those interstitial lung diseases cause fibrosis that is biologically identical to the fibrosis we see in idiopathic pulmonary fibrosis. And I think the fact that existing antifibrotic drugs have worked as well in IPF as they have in other forms of pulmonary fibrosis really speaks to the fact that biologically, these diseases are incredibly closely related.

And from a fibrosis perspective, we've got around this challenge of having separated our interstitial lung diseases into many separate categories. by coming up with the casual term of progressive pulmonary fibrosis. And really, that was a trick is probably the wrong word, but an approach that we took that allowed us to test antifibrotic drugs more broadly across a range of diseases.

Now when we take a step back and think about symptoms related to interstitial lung disease, these are really common across all of the disorders. So cough occurs with almost identical frequency across each of the different interstitial lung diseases. And the vast majority of cost that we see in the different forms of interstitial lung disease has a very similar biology, accepting that we don't fully understand the biology of IPF cough, but we do appreciate that it is caused in part by neuronal changes in part by changes in the compliance and stiffness of the lung and probably in part by an increase in mucus production by the bronchial epithelium and those mechanisms that are important in IPF are exactly the same in other forms of fibrotic interstitial lung disease.

And so I think in a long-winded way, what I'm trying to say is that cough is important across all forms of pulmonary fibrosis and interstitial lung disease. But the mechanisms driving cough are virtually identical across these different forms of disease, the morbidity and the impact on quality of life and everything I've told you about social isolation and stress incontinence is as true for non-IPF cough as it is for IPF cough. And I realize there's no such thing as a sure thing in drug development, but knowing that nalbuphine works as a treatment for IPF cough I can say with almost absolute certainty that it will work as a treatment for other forms of ILD cough. And certainly, as someone seeing these patients in clinic, the need for a treatment for cough is just as great in this group of patients.

And just to finally sort of give an idea of the importance of this group of patients, about 1/3 of the people I see in my clinical practice will have idiopathic pulmonary fibrosis. The other 2/3 we'll have other forms of pulmonary fibrosis and interstitial lung disease.

So for me, it's very important that Trevi has these plans to extend into ILD because whilst having a drug for coffin IPF is going to be important. I'm still going to be left with 2/3 of my patients for whom I need a treatment. So the plan to follow on very quickly with an approval study in institutional lung disease, I think, is both a very smart option from a drug development perspective, but is also a very important thing for me as a clinician dealing with the challenge of cough in my clinical practice. So I think I'll stop there, and if we've got time for questions, happy to answer them.

Wow, a lot of hands went up, Toby, but thank you so much. Every time I listen to you, I learn things. So we have some microphones here. Annabel, I'm going to start with you.

Annabel Samimy from Stifel. Thanks for the description between IPF and ILD and the similarities and differences. Just very curious about the study that would be conducted in ILD given that IPF is a severe, more aggressive, more rapidly progressive disease than some of the ILDs, if I'm understanding correctly. What is your expectation for the delta in the proof-of-concept study that -- or the Phase II that's being conducted. Does it need to be longer given that IPF is more aggressive, maybe they progressed more rapidly and had greater cost during that time period?

Yes. So I think that's an important clarification. So I think the rate of progression is important if you're developing an antifibrotic drug. So if you're developing an antifibrotic drug and you're relying on change of forced vital capacity over a given period of time, it is very important that your placebo group have a rate of decline that gives you a big enough window to show change over a specific period.

However, when we've looked at cough and myself, [ Phil Malone], my colleague back in London, he and I and our research group have looked at cough both in IPF and in other fibrotic lung diseases. And what we find is that, to a large extent, cough is independent of disease severity. So patients with fibrotic lung disease are either cough is or they're not. If you don't have a cough at the beginning, you don't generally speaking, develop a cough at the end.

It does seem that some people have a higher intrinsic susceptibility to coughing. And I think those are the people for whom cough becomes most disabling when they develop fibrotic lung disease. And so when you look at cough and pulmonary fibrosis, if you just look at cough count, it actually stays very similar over the course of disease, whether patients have mild disease or severe disease, the count is very similar.

The one thing that changes is the impact of cough on quality of life. So the impact of cost on quality of life is big with mild disease, it does become bigger when patients start to have coughing bouts that lead to oxygen desaturation that lead to them sort of gasping for breath. So the impact on quality of life does change over time, but the severity in terms of count doesn't. And so I think, again, it's a long-winded way of saying, actually, the rate of disease progression and disease severity in themselves are not important considerations for these sorts of cough trials that Trevi is designing. I think it's simply important patients have cough as a symptom. And if they do, then you're going to have a big enough delta between active treatment and placebo to be able to show an effect of therapy.

Go ahead, Kaveri.

This is Kaveri Pohlman from Clear Street. I was just wondering maybe connecting the dots between the biology of Haduvio and what you explained on the background of cough in connected to ILD and IPF. How much half and the intensity of it actually plays a role in lung deterioration by the mechanical damage, which can obviously induce cough and provide positive feedback or the inflammation -- re-inflammation you said? And do you think addressing that with something like Algeria given its biology, could slower the long deterioration process in long term?

And that's a really interesting question. And we don't fully know the answer. But again, interestingly, going back to the study that we did with our patients in London, we looked at about 600 patients. We have serial cough data on them. Most of it was visual analog scale because we weren't trying to do -- as you've heard about cough counting, trying to manually count cough counts on 600 patients at multiple time points would have been massively burdensome. But we use visual analog scale, which is a pretty good way of determining cost severity in patients.

And we did see that there was a relationship between cost severity and subsequent survival that was independent of disease severity measured by things like force fiber capacity. So that is tentative data suggesting that cough in itself is a determinant of mortality. There has been -- there's one other study published in the literature that showed something similar with this relationship between cough and survival. And so it is certainly plausible if you then join the dots that you laid out in your question that if we can find a way of suppressing cough, we may in turn improve outcomes for patients. And whether that is because we're influencing the development of fibrosis by reducing stress on epithelium, whether it's a sort of cardiovascular effect, maybe you're getting acute rises in pulmonary pressure with coughing, Who knows, but it is plausible that an effective cost treatment could improve survival.

Toby, do you have 5 more minutes for us? I know it's 8:00 a.m. Okay.

Yes, I can give you 5 more minutes.

A lot of interest in hearing from you. Alexa, Josh, do either of you have a question or no? We can keep it moving.

I know Leland and Judah, if the mic could go back to them. Oh, and Ryan, I'll come back to you. Oh, I'm sorry, I didn't see you. Go ahead, Roanna.

Roanna Ruiz from Leerink Partners. Just thinking ahead as a prescriber in the IPF patients and the ILD patient groups, where would you want to fit Haduvio into treatment paradigm? And think -- I know you mentioned Tyvaso as well if that's potentially approved in IPF, for example, and could cause some cough. How would you think about combining those products as well?

Yes. A good question. I think nalbuphine -- and I apologize, I'm still trying to get to terms with pronouncing Haduvio so stick in nalbuphine because I know I can say that without tripping myself out. I think as I would see it, it's something that sits separately to the antifibrotic drug. So my patients are going to come in with their pulmonary fibrosis. I'm going to want to put them on an antifibrotic drug to try and modify the underlying disease process. But if at the same time, that patient is complaining about cough as a significant symptom that impacts quality of life, I'm going to also want to treat that.

So I can foresee that we will use nalbuphine in parallel with antifibrotic drugs for that proportion of patients in whom coughing is contributing to their loss of quality of life.

And then as you say, Tyvaso is sort of an added wildcard because that in itself triggers the cost. And we've been using it for 2 or 3 years now as a treatment for pulmonary hypertension related to IPF. So we do have experience in this patient group. And really, the major reason for discontinuation is the coughing. And that is despite the fact that patients often see symptomatic improvement when you treat their pulmonary hypertension with Tyvaso. So I can certainly see a complementary strategy where a drug that helps to prevent cough could be used alongside a drug that treats pulmonary hypertension and fibrosis and therefore, is something that we would want our patients to be on. So I'm not -- one has to be a little bit careful about how one talks about these things, but I can certainly foresee that being a route that we would take in clinical practice.

Okay. We're going to do one more question, I'll get to some of the others of you in our next session. Leland go ahead.

Just quick -- this is Leland Gershell from Oppenheimer. Just a quick question for you in terms of market opportunity. as investors, we think about Haduvio out there once it's presumably approved, it sounds like the same frequency of cough in non-IPF ILD versus IPF and about 2/3 of the patients who have done IPF ILD. So in addition to that, being that non-IPF ILD presumably has lower mortality. Should we think about the use of be longer in each patient. So with the per patient use of Haduvio before more years than it would be for IPF given the relatively short life span those patients have once we're diagnosed. .

Potentially, yes. And if you're trying to model all these things, there's probably three buckets I would divide my patients into. So there's the IPF bucket, which is roughly 1/3. There's the autoimmune-related ILDs, which are roughly 1/3. And they're definitely the ones where there is a much better prognosis. So those patients are can expect to live for a decade or more despite their interstitial lung disease.

And then the middle third is the sort of mishmash of disorders that include things like hypersensitivity some of the pneumoconiosis, so things like asbestosis, albeit that's getting rarer these days. And then the various other things such as idiopathic NSIP and unclassifiable ILD that you will hear other people talk about. And that middle third probably has an outcome that better approximates IPF. So if we're saying 3 to 4 years for IPF, we're probably saying 4 to 5 years for that middle bucket.

So you've got IPF is the worst. You've got the middle of the bucket that's almost as bad and then you've got the autoimmune ILDs, which do have a distinctly better prognosis. And yes, for those patients, they will have a longer duration of symptoms like cough as well.

Okay. Toby, we're going to let you go. Thanks so much. We really appreciate you dialing in, and we'll send you off to your patients.

Good to see everyone. Have a good rest of the meeting.

Okay. We've got another equally a special gift in having Peter Dispan and guides join us. Peter is a Professor of Medicine at Albert Einstein College in the division of critical care at [ Montefiore ] Medical Center. He's got one of the oldest cough clinics he told me today in the U.S. He's also the Editor and Chief of Lung, and he also runs the American Cough conference every other year. So he is a very big name in cough. He's been very supportive to Trevi even I tell this joke, but when we reported our IPF cough data, I got a call from Peter, which, of course, I dropped everything and took and he said, "You need to study refractory chronic cough". And I actually had him present to our board. And so because of Peter's sort of passion around getting options for its clients, we are now sort of moving down that path.

So we're really happy to have him join me for a fireside chat, and he made sure there was a fireplace that I wasn't lying. And he's also going to be here for lunch. So we'll take a few questions and -- but he will also be here through lunch. So come out of Peter.

Those are big shoes to fill after Toby. I have confidence.

I can't matched Toby's beautiful Southern California accent.

So Peter, why don't we start off with you just giving a little background on yourself? I know I read from the slide, but maybe you can put it in your own words.

Yes. So as you mentioned, I spend -- I'm a pulmonary critical care physician. I'm a professor medicine up in the Bronx, at Einstein, [ Montefiore ], I spend a lot of time in the intensive care unit. When I'm not in the ICU, really going on 30 years now. I think I became interested in coin 1995 actually soon after I got to Einstein, and it's really been a focus of my attention, both in terms of patient care and clinical research.

I've started my cough center in 2003, and actually I'm up to over 2,800 patients that I personally evaluated with chronic cough. So it's a fascinating group. It's a tough group. And I'm happy to say that 15, 20 years ago, there were no pipeline cough drugs. And now we have maybe 6, 7 or 8 that I can think of off the top of my head, and that's all a direct result of us learning more about the mechanism of cough, learning about all the receptors and ion channels in the lung that are relevant to inducing the coughing flex. So it's been really gratifying, seeing us go from 0 to a bunch of Phase II and now Phase III trial. So really excited to have something in my hands soon that I can use.

Great. I'm going to ask a couple of questions, but then I'd love to bring the audience in. So think of what you would like to ask Peter.

Peter, I know it's been a journey even in sort of the 5 or 6 years we've been in it of how you clearly define these patients. And I get this question from investors a lot of what is this? Like is it just a bunch of junk, people haven't diagnosed what it really is, is refractory chronic cough really a thing. Our patent examiner is trying to get his head around that. So -- maybe you can talk about that because you've been on the forefront, I think, of trying to get this defined and the right patients.

Yes. So talking about anything, it's important to define what it is we're talking about. So chronic off is easy. If you've had a cough for more than 8 weeks, you have chronic cough. It doesn't matter what it's due to 8 weeks, it's chronic cough.

The refractory chronic cough is a specific thing. And that means it's a chronic cough that has not responded to appropriate treatment for the three main baskets of things that cause chronic cough. What we now call #1 upper airway cough syndrome, layman's term postnasal drip. The second basket of things is eosinophilic airway diseases, not just asthma, but there's something called non-asthmatic esaphilic bronchitis. And number three is GERD, acid reflux.

So if a person has been appropriately treated with the right drug at the right dose for the right amount of time and the doctor has appropriately ruled those things out, then and only then can you make the diagnosis of refractory chronic cough or RCC. And we're the small group of us in cough to do a lot of education to our colleagues at Grand Rounds and at conferences, we're -- we really stress these definitions because most of the drugs in the pipeline now are going to be labeled for RCC. So we as physicians are going to need to know when is it appropriate to prescribe these drugs that hopefully we'll have in the next 2 or 3 years.

And FDA has clearly become comfortable with that definition. So that's been helpful.

Another question I get, Toby just did a good job, I think, convincing everyone that this is a very burdensome aspect of IPF or ILD. And I think there's a perception that the cough and IPF or ILD is so much worse than RCC that RCC sort of less bothersome. I would love your perspective on that. I don't think that's necessarily true, but maybe you could share -- I mean, you see these patients.

Yes. It's bad enough that the lay community doesn't appreciate what RCC can do to a patient. But it's not an annoyance, it's not a pain in the butt thing. It's a life-destroying entity. So when I'm at my cost center, I very comment from me to see a patient who's been coughing every single day for 5, 10, 20 years, having been to a restaurant theater, it's a church, for 10 or 20 years for fear that one of their cough bouts is going to raise attention to themselves.

We did a study years ago showing that 53% of the folks coming to see me tested positive on a depression scale. Okay? So this is an annoyance that these folks are clinically depressed, as Toby said, they become shut-ins. The fats have gotten public for a fear of one of their cough [indiscernible] and that was before COVID. You can imagine what's going on now. So it's a problem.

But then it's not only the patient's life that's destroyed, there's a spouse in the picture. There are kids, there are coworkers. I have a lot of patients, very smart productive people who now either they get sent out to some corner office with the doors closed or they have to work at home or they've actually left work because they are so debilitated.

So these are things that really aren't appreciated because these folks become social isolated, so they're not really out there. Toby mentioned, urinary incontinence. So in women, we did a study looking at 210 consecutive women coming to see us at the cough center. 62% of those women had cough induced stress urinary incontinence. 62%. [indiscernible] [ cosyncopy ], fainting from cough is much more rare, but I do have a handful of patients that have such frequent [ cosyncopy ] that they have essentially become shut-ins because any time they have a bout of coughing, they can just paint. So you don't want to be waiting for the subway or driving when that happens. So we always try to teach our colleagues really how debilitating RCC can be. It's not just a cough. I don't worry about it.

Yes. That's helpful. And I always mention this, but in our RIVER study, we had one patient who cough 2,500 times a day. I mean it's really stunning how much they gave. Any questions from the audience? I can keep -- oh yes, please, Judah. We'll get you a microphone.

Judah at Morgan Stanley. Just curious on kind of standard of care here. How would you characterize it? How quickly do patients move through whatever you're able to prescribe for them? And then probably some stigma in the investment community around opioids being utilized. Just maybe some view on whether there would be any stigma from providers or from patients and maybe some insight into low-dose morphine being used currently?

Okay. The first part, I think it was just about the chronic cough folks in general. It's an extremely heterogeneous group, of course. I see folks who have been coughing only 3, 4, 5, 6 months, if they know about us up at mind if you or if they live in the neighborhood. So I'll see the cough for 4 months, but very commonly 10, 20, 30 years. Very often the eighth or tenth doctor they see.

And oftentimes, they -- we call it churn, they go through cycles. They go to their primary care doc. The primary care doc does what he or she can do then refers them off to pulmonary allergy, E&T, they go through that cycle. The cough isn't better, the medical system says to them, sorry, we can't help you. They go home than maybe a year later, they'll say, well, let me try this new primary care doc and then they go through that same churning cycle of the second CAT scan that they don't need. The second set of pulmonary function tested, they don't need, et cetera.

So very, very variable, really depending how lucky you are to be able to get into a situation where you've seen by doctors that are comfortable at treating cough. So it could be anywhere from a couple of months to decades. I think the second part of your question, I guess, was -- so really, the standard of care that, unfortunately, we still have to teach and drum into our Docs is that when act first meets the patient with chronic cough, their job isn't to say, well, here's a gefapixant that I got from Europe or here some Haduvio. No, the first job of a doctor is to do a thorough evaluation, looking for an underlying treatable cause of that chronic cough, upper airway cost syndrome, asthma reflux, treat that underlying cause and then make the cough go away. That's the best case scenario.

Then if that's not the case, you need to appropriately go through a specific algorithm where you can, with confidence, say, okay, I've excluded these things. There isn't anything I can fix then I have the diagnosis of RCC. So let's say we've actually made the correct diagnosis of RCC. In the United States, we have now, obviously, 0 options for treating RCC. We have no -- forget ours, we don't even have a drug for chronic cough. All right. The last -- does that mean when was the last cough drug approved by FDA. This is the audience participation part of the talk. Last cough drug by FDA, do you have one? Come on, you guys are cough folks. Last cough drug by FDA, 1958 extra credit, what was it? Benzonatate Tessalon Pearls, these nice little yellow gel through caps, very aesthetic looking capsule, very pretty. But those were approved for and then dextromethorphan was 1954, I think. But these were for acute subacute corps. So there's never been a drug approved for chronic cough.

Now in my teaching slides, I used to say that. Now I have to put parenthesis in the United States because we now have gefapixant in Japan and in Europe. So right now, we have nothing. So what do we have? So when we get to the diagnosis of RCC, the therapeutic landscape in the United States is #1 classic neo opioids, morphine, hydrocodone coating, not good options for something that may be chronic therapy.

So what we tend to go with is the so-called neuromodulators, amitriptyline, which is an old tricyclic cancer suppressant and gabapentin. In my experience, those two are very poor options because in my experience, maybe 15% to 20% of folks will actually have improvement in their cough from one of those two drugs. But the bigger problem is the patient has to tolerate the dose of the drug that makes their cough better. And especially with gabapentin, I have had tremendous difficulty with intolerable sedation from gabapentin. There's one randomized controlled trial showing the gabapentin suppressed cough in the U.K. They went up to 600 milligrams TID, which is unbelievable because I just try to get to 300 TID but I have patients that take 100-milligram pill and go into a coma and they can't tolerate it. So that's why our options are very poor.

And then we've also learned that the speech language pathologists can be very helpful as part of the chronic of teaching team, but there's very few of those folks around. So I might anticipate a future question by saying that when people look at some of the nalbuphine, they said, well, there's some sedation there, there's some constipation there. What I see there is much less bad than what I see with gabapentin, for example, where I see people that literally cannot tolerate even once a day 300 milligrams of gabapentin much less 3 times a day. where they are so sedated that they tell me, I mean, I just can't take it. So just to give a little perspective in terms of what we have now.

And Peter nalbuphine just to finish the opioid piece because I think it's important. It's a different kind of opioid. I think Jim did a nice job laying that out. hurdle is that going to be for doctors, for patients.

That was part three of your questions. Okay. Thank you. Yes. So any time there's any new drug, right, there's a lot of teaching involved, right? So when the first pulmonary hypertension drugs came out, we had to remind doctors what they had learned about in med school, but then forgot because pulmonary hypertension had no treatment. It's a terrible disease that killed young women. But then when the first drug came out, there was an opportunity for teaching.

For nalbuphine, there'll be two levels of teaching. One is just to teach about what we're talking about chronic of and what is -- but also, we're going to need to remind our physician colleagues about what they learned in second year medical school and pharmacology class, where there are different opioid receptors and the ones we're most familiar with are the drugs that are [ MU ] opioid agonists, morphine, hydromorphone, coating, et cetera. And those are the ones that carry all the bad baggage and about which we are fearful.

So we're going to need to then teach that now been seems to have its antitussive effect through the [ CAPA ] receptor agonism. And interestingly, it's a mute antagonist. So -- that's going to be very important teaching for our colleagues to say, "Oh, well, yes, I mean it's an opioid because that's a general term, but [ MU ] and [ CAPA ] have very different meanings and different pharmacological issues. So the teaching is going to be necessary.

But then the thing is, I always come back to, well, what do I have right now, gabapentin, I've had huge amounts of problem with. So in terms of intolerable side effects. So I think other physicians that have similar experience would be happy to try something that appears to have less side effects, at least in my experience than wood gabapentin or even sometimes amitriptyline.

Great. Ryan?

Curious on what in your experience with your patients, time to diagnosis looks like -- and speaking of some of the antitussives that are out there, Tessalon Pearls and gabapentin, are there certain patient subgroups where those work better than in others?

Yes. The first question is literally unanswerable because as I said, I'll see someone who's been calling 2 or 3 months and other times, I will literally see people that have been coughing for 20, 25 years. So really depends on how fortunate or not fortunate they word who have gone through an appropriate workup of chronic cough before coming to see me.

By the time folks have seen me, they've tried everything. Benzonatate really is like a coin flip. It works for 50% of the time and someone who has I would recall that an acute or subacute cough that is always due to respiratory tract infection. As I said, it's not a proof of chronic cough. So they've tried to dextromethorphan, benzonatate oftentimes short courses a coating given by their desperate primary care Doc. But there's nothing reliably that works.

And as I said with I'm a triplane gabapentin, the two so-called neuromodulators that we use, they're off label, but we have nothing for chronic off in the states. My experience has been very poor, both in terms of their efficacy and tolerability.

Kaveri?

Kaveri Pohlman from Clear Street. Just a follow up on the standard of care options. So let's say, if Haduvio is available tomorrow to you, how many step-throughs you would expect for the drug as well as how many patients would you give it to? And any comorbidities in the patients for which you would avoid giving this drug to just kind of like starting with that.

Yes. So remember, when you have 0, anything other than 0 is good. So the day the first drug for RCC is approved every single patient with RCC would be a candidate for that drug, whether it's [ gefapixant ] or nalbuphine Why? Because we have nothing approved. So the first RCC drug will be appropriate for everyone. With nalbuphine, I guess I would be -- I would make sure to see what other drugs the folks may be on that may be potentially sedating. So that will be something I would keep an eye out for.

Got it. And maybe a quick one on the metrics. Obviously, there are a lot of -- there's a primary endpoint and there are key secondary endpoints. What are some of those metrics you would really like to see to really drive the -- that can drive the use of Haduvio.

Yes. So cough is interesting, right, because it's cough has both a measurable objective component and the subject of component, right? If you're doing a blood pressure study, while your BP at 122 over 82 or it's not, with cough, we have -- the FDA wants us to measure cough. But regardless of whether the cough count comes down, you really want your patients to say, "I feel better". So there's both a subject of an objective component. So to get the drug approved, we'll need to give FDA both objective and subjective. But when we are dealing with the patient and what the patient tells us is the important thing. Do I feel better with this drug is my cough better? And am I tolerating the drug. And it's really as simple as that.

And about last question from the audience, then I have one question I want to ask.

I guess, just to get a little bit more granular on how you might position Haduvio relative to, say, P2X3s that come into the market earlier. So Haduvio shown activity across the spectrum of severities and PTX were primarily severe. So when you see a patient, how do you determine whether there are severe, moderate weather P2X3s are the right way to go? Do you have to step through the P2X3s before you give that severe patient or that moderate patient the Haduvio, just thinking about how you really rank these patients?

Yes. Well, if they're in my office, they're severe, but that's because I run such a cough center where I see these folks. But I think the most likely way things might play out, for example, is, let's say, candidly [indiscernible] gets approved first, which seems perhaps likely. We know a lot from gefapixant and [indiscernible] that there's at least a 30% nonresponder rate with the P2X3 drugs, but that's true for a lot of drugs, right? I don't have any drugs that have 100% responder rate.

So there's a large nonresponder rate with the P2X3s. And even the responders, they don't go from a bunch of costs to 0. They go from a bunch of costs to a lower number of costs. The P2X3 are not light out drugs. So let's say, if nalbuphine is the second drug approved, we will already know what [indiscernible] can or can't do. And again, these are not light sale drugs. I think gefapixant might not be as effective as -- may not be as potent as [indiscernible], but we'll see. But there'll be a lot of nonresponders and partial responders. So any second drug that becomes available, it would be appropriate to see if that drug is better, either as an add-on or an instead of.

But that brings up a more important point, and that is peripheral versus central activity. right? So there was a nice -- I think Jim showed a nice figure where like in the lung, there's all kinds of receptors, right? This P2X3, there's [ TRPA1, TRPA4, TRPA8 ], voltage-gated sodium channels. So the RCC patient, in my opinion, is a very heterogeneous group. One will have a cough due to a P2X3 relevant mechanism. Another will have a NOV17-voltage-gated mechanism. So if you're using a peripherally acting drug, then you're hoping that, that patient's cough is due to a peripheral mechanism that's relevant to the drug like ATP stimulating P2X3. But if you have a drug that's predominantly central acting, right, then that drug is agnostic to which particular receptor got tickled P2X3, voltage-gated TRPnA1, et cetera.

So that's why, to me, it wasn't surprising that the nalbuphine data were not only was the core frequency reduced to a great extent than any other drug we've seen but high and low cougher across the board responded similarly to nalbuphine and that's again what I would expect from a centrally acting drug.

Way before Trevi existed when I asked the question, I said I would ask, what's the ideal cough drug. And I would say, well, essentially acting drug that isn't a classic MU-opioid that doesn't cause a lot of sedation because, again, if you're using a central drug, that drug is agnostic to which particular ion channel receptor happens to get stimulated to start the afferent mechanism of cough.

And great minds think alike because Annabel, that was my question. Josh, we're out of time, but I'm going to give you one because I want to bring you in. So go ahead.

Joshua Schimmer from Cantor. Do you need both the CAPA agonist and the MU antagonist effect to impact the cough. And if not a question then for Trevi, would you have any life cycle extension plans to isolate the active component?

So not being a pharmacologist, that's a little above my pay grade. But certainly, from the data we've seen, you have to assume that the CAPA agonism is responsible for some, if not most of the [ antitussive ] effect and then whether there's any MU involvement because there's an agonist antagonist situation going on there. But again, not being a pharmacologist, I don't think I can do justice to the question.

Yes. I think we believe, Josh, it is due to the CAPA. We're spending a lot of time on IP now thinking about the next generation, Tom, my co-founder, has been doing a lot of that. So -- it's a good question and more that we'll share over time as we move forward. So thank you for the question. With that, I'm going to wrap up this section, so we can keep moving. Peter, thanks so much. And he'll be here at lunch. So feel free to sit with him and ask more questions.

I think you get rid of me at this point. Yes, I'm going to turn it over to Farrell to take you through our commercial work that we've been doing.

Thank you, Jennifer, and good morning, everybody. So what I hope you take away from today's presentation are two main things. We've been deep in research with physicians and payers better understanding the IPF and ILD landscape. And we've also talked about a lot of the market opportunity, and we've dug into what this addressable TAM is that Jennifer laid out as well as what we believe we can achieve and penetrate with Haduvio.

You saw the nice patient testimonial campaign that we're kicking off today. It really goes to exemplify that it all begins with the patient. These patients have a chronic cough that's debilitating that's isolating and that's impactful to their lives, but also their livelihood. And when you look at this, they have no options. It's a persistent cough that requires a chronic therapy.

And so we did -- we look at the commercial strategy through that patient lens. And there's a couple of areas that you heard today, you heard from the KOLs, you heard from Jennifer in the upfront. We are operating in large underserved markets. There's no approved therapies in any of our categories today. We have a very differentiated clinical profile for our drug that is perfectly matched to the population in which we're treating. And we're positioned to become the first approved IPF chronic cough therapy and have the position to become best-in-class as well.

There's a nice scalable extension from IPF to non-IPF ILD and RCC, which I'll walk you through, how we're being diligent about that and how the factors that we're taking into account in IPF really do translate across these three patient populations. And lastly, the compelling specialty model that we'll deploy. We're being very diligent and disciplined about that specialty model and how that is addressing this $30 billion plus TAM.

So we had -- we did a piece of research in partnership with the Pulmonary Fibrosis Foundation in the U.S. These are 2 -- approximately 200 patients from their community registry. And what you see here is the striking burden of chronic cough among these patients.

78% of them, once they begin to cough call for more than 30 seconds. These are these cough bots that Toby and Peter talk about. This is what impacts these patients and brings them a lot of times to their knees. And it's really impactful to hear that from those patients because these are the things that make them socially isolated physically exhausted.

What's also impactful here is just the dissatisfaction that you see. 2/3 of these patients are not satisfied with their current or prior therapies, and that's consistent across the work in which we've done. So these are a patient population, and this is among ILD patients. So as Toby talked about, they're very similar between IPF and non-IPF ILD, but it's consistent across the ILD population.

And from that same piece of research, just echoing some thoughts that Toby had, these patients, when they self-assess their cost severity from the date of diagnosis to where they are today after a couple of years, they are either the same or worse. So cough doesn't resolve itself in these patient populations. And 76% of patients with chronic cough will have had their chronic cough for greater than 2 years. So this is something that hangs around these patients and worsens, which just exemplifies the need for chronic therapy.

You heard about the quality of life impact, which is pretty consistent, I think, easy to understand of the physical, the social, the psychological impact, but it goes beyond that. There's a nice piece of work from the Pulmonary Fibrosis Foundation Registry that links a worsening baseline cough to worse health outcomes. That's a worsening respiratory hospitalization, increased risk of mortality, but also its increase of specialist visits.

So this is not just about a quality of life story. This is about a medical necessity story and treating the constitution of the patient. This is a measurable impact that not only impacts the patient but also impacts their daily function and health care resource utilization.

So this is a slide I'm going to pause on a little bit and really dig deeper because this is -- really when we look at IPF and the core of our strategy, as Jennifer said, we're an IPF led company. And when you look at the market reality of the dynamics, there's no approved therapies there's a significant burden in these patients with a high quality of life impact and the antifibrotics, most importantly, do not affect chronic cough.

So physicians right now, and you heard from Toby, and you heard from Peter, trial and error. They're trying different things, seeing if they work with certain subtypes of patients but unfortunately, failing most of the times. Patients are also frustrated within that same feedback loop. And so patients haven't removed themselves of their markets. They're continually seeking out providers and professionals to help them. They want an effective therapy, and physicians are ready to adopt that effect of therapy.

And the system around that also utilizes it. Pulmonary Fibrosis Foundation, I'll show you in a minute, has a concentrated set of centers of excellence, and that plays right into our specialty commercial model.

So we believe we can achieve rapid adoption as first-line therapy among IPF and ILD patients where nothing else is available for these patients and that we are going to be early in the treatment algorithm across all of these conditions.

One of the core to this is our specialty pricing because of the small patient population, which we'll launch with IPF and take into these additional populations. So this is a scalable growth model that we have without incremental commercial complexity.

And the competitive landscape really reinforces this. This is a competitive landscape in IPF and ILD chronic cough where you see a number of failures and Haduvio as the only therapy left in development and late-stage development. The reason being a lot of these have been these peripheral-only agents. They're trying to work at the lung level in this fibrotic tissue, and they haven't been able to demonstrate any efficacy, including some of the antifibrotics that have been studied here. So we have that central and peripheral component, both of which are important here that enable us to have the potential to be first-in-class and best-in-class across IPF and ILD, one in the same patient population for the most part.

And when we did a lot of research over the last year. This is a piece of market research with 90 pulmonologists in the U.S. This is how they look at the market. They looked at -- this is pulmonologists from the academic care centers from those care centers as well as community pulmonologists. And you see here the rating of the unmet need as well as the impact on quality of life is rated extremely high here, very rarely see scores from physicians in the 8s.

And the reason being is they recognize this patient. They know this patient when it walks through their door and they know they don't have any therapy today to enable to treat that patient effectively.

And so you see some of the quotes here, and I think it's some impactful language that you'll just read, there's a very high unmet need. Chronic cough is often a major driver of clinic visits and contribute significantly to patient dissatisfaction making effective treatment options critically important. It's a major driver of clinic visits. So these are our target pulmonologists and they're ready for a therapy within this space.

This is the category before we showed them our product. And when we translate and show them our target product profile, we ask them on three dimensions. The X access is efficacy, the Y access is safety and the size of the bubble is tolerability. You see a clear superiority of Haduvio versus what they're using today. Superior on efficacy comparable safety and tolerability.

And this leads directly into intent of how do physicians intend to use this and what patients they intend to use the same. So it translates into greater than 50% of their IPF patients at peak, they intend to use this in. It's a critical mindset shift once they have an effective and safe therapy versus what they're using today.

One of the quotes that one of them gave us this should become a standard treatment essentially as a first-line option. So they're already positioning this as early treatment and not as a last line resort. And it shows up in how they intend to use it in their IPF population. So this is the same 90 physicians about IPF, they want to use it as combination therapy with those antifibrotics. And you heard that from Toby earlier. It naturally is used with that product because you're not impacting the underlying disease, you are impacting the overall patient. And we heard in other pieces of research some physicians would even look to initiate Haduvio before an antifibrotic because the patient is going to feel better, and they know they're going to feel worse on an antifibrotic. So they can get a quick win with these patients.

And then where in the treatment algorithm do they anticipate using this as either first or second-line therapy. And that's where we anticipate being used in IPF and ILD. So there's confidence -- it builds our confidence behind the rapid uptake. And when we look at that uptake curve, that access builds quickly. We expect prescribing to begin rather rapidly and to mature within about 2 years. And that is expected because of the access landscape and the lack of available treatment options here. So it's consistent with other special respiratory launch items in areas of high unmet need.

So that's a lot of our physician work that we've dug into over the last year. We're now transitioning over to payers. And we've talked to 15 payers in the U.S. that cover most of covered lives across books of business. And what's striking here is the similarities that we received from payers and their responses to what we saw from physicians and pulmonologists.

They recognize the unmet need. They recognize that no therapies are approved and that they're not effective and that current treatment options are inadequate. And that translates directly to the difference they saw when we introduced Haduvio. They actually see probably more separation of Haduvio versus what's used today because they see patients cycling through these therapies as well.

And when you look at what payers feel as important measures to themselves, there's really three things. It's a clean indication, credible and reliable efficacy and durability and as well as predictable utilization. And Haduvio is able to deliver on all three of those metrics for payers.

And that translates into our pricing corridors of where do we anticipate pricing to price IPF at launch. And we tested $75,000 to $125,000. And across this entire range, you don't see significant difference. Pricing is rather inelastic. And that's because it will use utilization management in order to restrict us to label enable prior authorizations and require step throughs. But this is the same framework that antifibrotics are on today, specialty tier, step-through therapy, first line though, and patients get covered. And so we expect to be right where antifibrotics are in an established framework with no new access model. This is very familiar to payers.

So that's the IPF story. Now it's how do we efficiently expand from IPF into this non-IPF ILD category? And you heard from Toby earlier physicians see these categories as almost one and the same. There's been a lumpy and a splitting of ILDs over time. I feel like the pendulum is almost swinging back to a lumping of these patients because guidelines treat them similarly, the patients present similarly and they present to the same providers.

So this is not a new market build for us. This is an extension using the existing infrastructure that we have which is part of our capital efficiency approach of how we actually access this market.

So from a commercial standpoint, there's not much change here. Similar patients majority of them cough that you heard from Toby across this patient presentation and comparable severity and quality life impact as to IP. The thing to note, IPF is the most common form of ILD. So it's almost our test case as we go into this broader ILD category.

And physician setting the pulmonary fibrosis care centers in the United States are ILD care centers. They're not IPF care centers. So where we're going to be already in IPF will already have covered ILD.

And lastly, the same treatment paradigm. We expect same guidelines to be treated across these patient populations, and we expect payers to manage access similarly. We performed a research a number of years ago, just looking at physicians, this is U.S. physicians about how they view these patient populations. The bottom line is they see this as the same patient. And our commercial model and what it looks like in practice are these pulmonary fibrosis center care centers. about approximately 90 care centers in the United States and growing. And that's an important piece that as they grow their care center network, this concentrates our patient pools to actually make it easier to target over time. And so they added, I think, 10 of these centers over the last year or so, which is great to see. And that enables us to efficiently target them with a field force of 50 to 75 reps at launch. So we're -- this is where our operating leverage comes from.

And it's hard to see within this but this is the anticipated adoption between the two indications: IPF and non-IPF ILD, there's actually two lines here. But they mirror each other one on top of the other, because it goes back to the same thing that this is the same type of patient that's presenting to the same type of physician.

And I think Toby did a really nice job of just reinforcing the patient population of how much of this is IPS versus non-IPF. And how much do we think we're able to build out in terms of this addressable patient population. It's roughly 1/3, 2/3, there's greater than 350,000 in the U.S. ILD patients that would be core targets for us with chronic cough. Same engine, but we extended to a much larger base.

Pricing always comes into focus in terms of how do we take pricing from our IPF specialty led market into these other indications. ILD is a natural extension from us and their strong precedent from the antifibrotic space. So antifibrotics as they launch or as they expand, they maintain the same list price from IPF to that broader category of PPF. And that's exactly what would be expected of Haduvio to maintain that same specialty pricing across IPF and non-IPF populations. It's still seen as a rare disease in payers' minds, which allows us to occur.

So those are the first two areas. The last area here is refractory chronic cough, and we're taking a different approach to Refractory Chronic Cough. We're not going after the mass market primary care RCC market. We're going after those who have failed multiple lines of therapy, one to two lines of therapy, which may not be working and one of those may be a P2X3 doesn't have to be. but it's an even larger opportunity by doing so.

So when we look at RCC programs, the competitive landscape is similar. Multiple failures because of that peripheral nature of that disease, but that central component matters. And so Haduvio is well positioned within this space, perfect for those who have failed other therapies that may be off-label. And we go back to that piece of research of -- I think John asked the question, are they seen as any less severe? These patients are seeing just the same in terms of what is the impact that chronic cough has on their lives. It is just as severe in terms of the unmet need, the importance to treat or the impact that it has. And so the commercial approach translates well with a primary call point as pulmonologists.

And so the different approach that we're taking in RCC is going after these -- the subset of them that have treatment-resistant disease. Those who have failed one to two other lines of therapy, those were specialty care is already engaged with the same core field force with pulmonologists as that call point. Same pricing dynamics and focusing on those patients with the greatest unmet need.

And it really comes down to access. This is probably the largest question I get commercially about how do you then translate the price from IPF and ILD into RCC. And it really starts with what will already have been established in the market and how do we leverage our payer familiarity in order to extend into a subset of the RCC market. So it builds on what's been established, coverage positions, formulary, prior authorizations, access pathways. These are all scalable and have been established through IPF and ILD that will be transferable to an RCC market. And what we'll look at is this subpopulation, and I'll get into the TAMs in a second. So we're not looking at a new framework here. We're looking at an extension but derisk the payer for a manageable, predictable size of this market.

And so when we roll it up in terms of the overall total addressable market here, you see the eligible patients up top, those are the underlying disease itself, the eligible patients being those that are uncontrolled chronic cough. And factors of our specialty pricing, which we'll launch and take into these indications as well as the expected gross to net. And Jennifer already mentioned the large TAMs $5 billion plus in IPF, $7 billion plus in non-IPF ILD and $20 billion plus in treatment-resistant RCC.

Question is then what can we achieve as Haduvio. When we look at IPF, we can achieve a large market share being the only first-in-class, best-in-class therapy, 25% to 35% share. Similarly, in non-IPF ILD. And we purposely took a modest 3% to 5% of the treatment-resistant portion of RCC. These build these into $2 billion franchises for each indication, a $6 billion franchise at total peak sales across all three.

So what I'd like to end with is just pulling this all together is we're operating in large underserved markets, no approved therapies. We have a strong differentiated profile, and this is transferable and scalable between indications without additional complexity via a streamlined approach that we can take with pulmonologist has a clear call target. So a clear line of sight to value creation.

With that, I'll turn it over to Dave.

Well, thanks, Farrell. I like my numbers in the billions, and that was very exciting. Good morning. Great to see so many familiar faces in the audience today, and thanks to the people listening on the webcast. I've been subject to a fair amount of ribbing the last couple of weeks from my colleagues at team Trevi, because I was given the burden of actually presenting and preparing one slide today. So I better not screw this up. But moving on here.

I really want to focus is on the financial foundation today at Trevi, which I'm pleased to report is quite strong, particularly after our successful follow-on offering we completed in April. We raised [ $62 million ] in net proceeds, and we're really pleased with the support from our current shareholders, and we thank you. And we were gratified to welcome new shareholders to the Trevi story. So a very successful follow-on offering there.

And if you couple that with the $162 million -- $72 million, we reported a couple of days ago at the end of [ 331 ]. We extended our cash runway into 2030. And importantly, that drives a lot of clinical value for Trevi. So with that runway, it buys us, of course, the two Phase III studies we're about to embark on. through NDA filing and potentially FDA approval, our lead indication.

In addition, it buys us the IIb and potentially a Phase III in the non-IPF ILD indication and we'll buy us that top line data. And then, of course, it buys us the RCC Phase IIb data. Now we're not funding our commercial expenses or other clinical trials with those proceeds. But what we did accomplish with this finance is removing the financial overhang as we report out this data. That was our clear objective and one we've met.

So with that, I'll stop. I turn it over to Jennifer.

You nailed that one slide. Jim has been ribbing about that for quite a while. We're in the home stretch, two more slides here, and then we'll do a little bit of Q&A.

So IP, I want to just spend a minute here. We've been investing a lot of time and resources into protecting this I personally become very convinced this drug works. I think Farrell did a really good job of showing you this is a big market opportunity. So I think our ability to protect this and extend the patent life around this is really key in driving tremendous shareholder value.

So I put a team against this sort of early in the year. My trusted sort of co-founder here, Tom, it's his full-time job to think about the next frontier of patent. So Josh, these are all great ideas, keep them flowing. It's being driven by Tom. We had a long-term IP patent lawyer at Cooley, who retired. We went and pulled him out of retirement. He's working with us now drafting claims and our Cooley team who prosecutes our patents.

We also brought in a very distinguished IP litigation firm and rather than engage them on the back end when you get a Paragraph IV filing, we brought them in now to look at our patents, advise us on how strong they are, where we need to be shoring them up, and they're thrilled to be working with us. They've been incredibly helpful.

So just to explain to you our strategy, and I've been in this method of treatment world, my entire career, and composition of matter is easy because nobody has to think.

Method of treatment patents can be just as strong. You just have to be thoughtful about them. So as you can see from this slide, we've got our broad foundational patents that have either been issued or in late stage. So the method of treating IPF cough with nalbuphine. It's very hard for a generic to get around that unless you've got gaps in your patent.

The IP litigation firm I mentioned was engaged last year to look at those patents and then come back to the Board and myself and tell us how strong are those patents. We got a very good thumbs up on that. So I have a lot of confidence that these are well protected through 2039.

So now Tom's mission is to essentially take that 2039 benchmark and extend that runway. Fortunately, because we're now -- we now have clear line of sight around our label, we're able to now start building around these label claims. So dosing in hepatic-impaired patients for the actual titration schedule Jim took you through a lot of Phase I work going on formulation work going on. And anything filed for instance, this year in 2026, those are 20-year patents that they get issued. So that takes that 2039 benchmark to 2046.

So what I can assure you as investors and analysts in the company is a very high priority for Trevi, and we have 3 years to continue to invest here until this drug gets launched, and we will continue to build out this patent estate.

So last slide, you've heard all this today, but there's a lot of data coming around. So we mentioned that we're going to be starting Ocean 1 and the RCC study this quarter. We have a couple of our clinical people here. You'll recognize them. They're the ones with bags under their eyes because they haven't slept. They've been working really hard. We'll give updates on those on our quarterly earnings calls, how they're coming along. We'll initiate our other Ocean Phase III study in the IIb and ILD kind of right on the heels of this second half. We're really hustling to get to an SSRE readout by the end of this year in RCC. Those are pretty telling. You get halfway through a study and you get a readout on is this drug working? Is it futile? Is there an upside? You can sort of read between the lines on what where we're heading with that. And then three key trial readouts in the second half of '27.

So our second Ocean study, the 12-week study Jim took you through, we'll get the first look at the Phase IIb and ILD. So that will be telling about what that Phase III trial looks like and then the full readout from our RCC trial in the second half of '27.

Then our larger Ocean 1 trial will read out the first half of '28. Jim has got his team focused on roughly 6 months later an FDA submission. And so we would look to if you roll all these time lines forward a launch in late 2029. So we're pretty excited about it. I joke. Tom will appreciate this. We may live to see this drug approved, Tom. There were days of my life, I actually doubted that, but it's been -- yes, run I threw the coin and the Trevi fountain. So anyway, with that, I know we're right about at noon. We're going to just take 10 minutes maybe for questions so I can get people out of here on time. Our whole team will migrate to lunch, so feel free to spread around, including our -- even the rest of our team here. So I'd like to invite the speakers up to the stage and please raise your hand if you have any questions you want to ask. So why don't you bring the mic up, Josh will give you the first question there.

Thanks so much. This is a really good event. Really enjoyed Dave's slide.

Do you see a path to a broad cough label maybe carving out those who have some kind of a reversible component to it? Because you just kind of keep running the same study with the same results over and over?

Jim, I'm going to give an answer because we talked about this early on, but I want you to answer. Jim's been the kind of the latest entrant here.

I don't think so, Josh. I think the FDA is very focused on specific patient populations. I think that an IPF patient is quite different than an RCC patient, even though chronic cost sort of underlies it. And Tom and I heard in the early days with the FDA, that was not something they were particularly interested in, how things evolve over time. So Jim, I'd love you to give your views on that as well.

So Josh, I think the key is really that the way the FDA thinks and I've seen this across multiple divisions over my years is like they'd rather be more specific than go broad on the indication like this. So Idea, putting the trial in the context of specific populations like IPF. It allows the division to really look at it in relationship to the specific risk benefit as it relates to that. And as you can imagine, RCC population versus an IPF population from the FDA perspective, might have very different risk kinds of benefits. And so I think that's where we need to think about this.

Which is why I think it makes it difficult to think about this broader label. I mean we've seen this in the sort of broader pain context and other things where you can play across different types of populations, but I don't think that's really the way the FDA thinks and I've seen this across multiple divisions.

Even though these are already very heterogeneous conditions, refractory chronic coughing we heard like 200 different etiologies of [indiscernible].

Yes. And I think that's where the key is, right? I mean there clearly are more specific populations that. We get to first.

Ryan, and then you can hand it back to Judah when you're done.

Curious what the Trevi team has seen so far on urinary incontinence with Haduvio so far? And then for Dr. Dispan guidance, how are you thinking about breathlessness in the context of RCC, how important that is?

Jim, why don't you comment on that.

I'd just say that briefly, I mean, we're going to be really measuring that more seriously now coming into these trials. So I don't have a lot of basis to really talk about it. .

Peter?

So as far as the breathlessness, so the RCC group is interesting. RCC patients, the classic RCC patient is a woman in or 50s or 60s chronic cough centers, like mine, 2/3 of the patients are women. Women have a more sensitive coughing flex. So across the board, it's a female-predominant thing in RCC. But these folks oftentimes are otherwise fairly healthy. They typically have normal lungs, not too much in the way of medical issues, just the RCC has destroyed their lives. So breathlessness tends not to be a problem, except when they're in one of their prolonged coughing bouts where, obviously, then your shorter breath.

Very different than the IPF population, which is mainly men in their 70s who have smoked for decades. So they're older, more frail group. The RCC group is typically a healthier group that for whom RCC really is the main issue.

Judah from Morgan Stanley. I guess now that we have your answer on kind of breadth of the label, and we appreciate all the work, Farrell's done on commercial opportunity. But we hear estimates out there that non-IPF chronic off could be significantly higher in terms of epidemiology than what we think right now.

So I guess, is there upside to the addressable market in non-IPF ILDs? And kind of could incidents and that indication be significantly greater than what we know it is today. And then in a world where Haduvio is approved in that indication, could you see that encouraging increased diagnosis?

So it's a great question, Judah. The way we arrived at our non-IPF ILD population is we did a targeted literature review of the specifics, not all 200, but call it the top 100 of those individual disease states, and try to characterize what proportion have a dry chronic cough as part of their presentation. So that's how we arrived at the, call it, $228,000 in non-IPF ALD I think as we get into -- it was not claims-based as we get into claims data, yes, that number could change. It could be larger based on the experience that Toby had as well, but we'll refine that as we get closer to launch.

Okay. Yes, Brandon, you haven't gotten into this. So I hand it back on.

Brandon Folkes, H.C. Wainwright. Maybe just following on that. In the RCC population, how do you think physicians are going to view gefapixant partial responders if Haduvio is approved as? Are you going to view this as a treatment success and keep the patient on therapy? Or could you move them to Haduvio?

So if a patient has a terrible cough and they have a 20% improvement with, let's say, gefapixant, that's not going to be good enough. So then the question is, do you try -- do you add a second agent or simply try a different agent.

In my mind, again, a centrally acting agent is agnostic. So I wouldn't add nalbuphine to gefapixant, I would exchange it for gefapixant. But you can use both together. The proof is going to be once both drugs are out there. But theoretically, a centrally acting drug is going to trump the peripheral so I would exchange rather than add on.

Yes, will end up behind you, Brandon, she hasn't got a chance. Thank you.

Thank you so much for the presentation. My name is Abney. I'm asking on behalf of Debanjana from Jones Trading. Are there any specific commercial lessons that you're drawing from [ Insmed's Brin ] Super launch around pricing strategy, payer engagement, patient physician education and how that relates to Haduvio.

Short answer, yes. I think [indiscernible] you had a phenomenal launch, I think, for [ Verona ] also had a really strong launch in respiratory. What it comes down to is it comes down to access. And we need to shape the environment and that's both from a burden of disease of the patients, which is the start of the patient testimonial campaign that we showed here today, but it's also early payer engagement and how do we build the strength of our value story from our clinical data to that -- to the patients in need. And we will be -- we have and we'll continue to dig into that launch so that we are set up for success.

Okay. Maybe hand it back up. We'll get over here to Roanna. I'll get you too, and then we'll wrap it up.

Roanna Ruiz from Leerink Partners. I was thinking about the non-IPF ILD study that you're going to gear up? And anything special you need to think about in terms of inclusion, exclusion criteria of finding the right patients knowing that ILDs can be a basket of many different types of patient groups.

So it's a great question. We actually had an incredible advisory board on this a number of months ago actually last year because it is a complex population -- and I think there was a big aha moment when we were really bringing this out with a bunch of the experts in this space is that the defining characteristics and Toby said this, is that they have a certain amount of lung disease and they have cough. So if we ignore the basic population comorbidities that can occur with these underlying conditions, people with RA or [ Shogan ], et cetera, really comes down to how much fibrosis do they have cost do they have.

So we're going to take a very unified but simple approach to that study, and we're going to be identifying patients that have, regardless of the comorbidities and maybe [ CONMED ] that we have to sort of figure out some details about but it's going to be people will have a certain amount of fibrosis in the ILD category and a certain amount of cost. So I think it keeps it sort of across the board, it's going to be focused on the essential elements.

Annabel?

So appreciate the market analysis you did for RCC. Is there any further thought to brand splitting? I did notice that you had a 27-milligram QD there, which, yes, minimally tolerated dose, but was that for a different reason. And one more question.

So when we look at the difference in total daily dose between IPF and ILD, which I think is sitting up here, we expect to be in the same range of dosing. To a potential RCC that may be a much lower dose, maybe a 27 QD, there is potential for brand splitting.

Now it doesn't mean necessarily pricing on a per milligram basis. We'll have to do a lot more work on that. but it does allow us to maybe access more of the RCC market by doing so without [ SAC ]. The one thing we will not do is sacrifice pricing or cannibalization in our IPF or ILD market.

Okay. And then the second question, when you're laying out the pricing. I noticed one step edit, two step edit. We're talking about IPF and ILD where there's no approved therapy. So what do you expect that step at it to be?

Off-label therapies the standard of...

How do they establish that?

How they establish standard of care versus what they're using today. So [ Tesonpearls ], neuromodulators, pretty much what they're using today in that environment.

Okay. Bring us home, Kaveri last question.

Kaveri Pohlman from Clear Street. And thanks for hosting this insightful event. It was very helpful. And one question, perhaps maybe for Jim. There are some publications suggesting that targeting P2X3 impacts the expression of opioid receptors. And so I was just wondering if you can provide any insight on how and if P2X3 antagonist could impact do you use efficacy if there's any biomarker data or in literature that can....

That's a tough last question.

I have another one after.

I don't have any direct evidence on that. I think as we look at this and whether or not there's going to be a combination therapy, as Peter says, I mean, I think there's going to be the likelihood that in the RCC population, it may be in either or situation.

I think the key thing to come back to is that the central component for what Haduvio does is really the critical piece of our activity. There may be things -- obviously, there's efficacy data with peripheral acting drugs. But I think as you focus on P2X3 mechanism or some other mechanism that may be more sodium channel related or something like this, we still bring it together in the brain where there's a simplification process and where maybe we have the opportunity to damp it down.

I don't have any direct evidence that P2X3 activity, which we know there are receptors in the brain, those drugs don't work there. But I don't know if we have any evidence that would suggest that one would affect the other.

Got it. And maybe the second one, it's very simple. The -- there were some previous discussions to study like the QD potential for Haduvio in Phase IIb RCC trial beyond the titration period, obviously. I was wondering if that's still off in trust, that's something you can probably do in the future?

For RCC and the Phase I, we have the QD dosing for 27. That will be our first insight around that. If it looks like for any reason that RCC has much lower dosing, which I don't know, Peter, you may have views on this, is a possibility. RCC is very different, I think, than fibrotic lung diseases. So if we start seeing that, we're going to go back and explore the really low end of this dose range. And our colleague, Steve is in the room, but he's out working on much lower dose formulations which could open up a whole another opportunity to really go out the market separately. So we'll just go where the data takes us.

Yes. And I think just one addition to that is that when we think about it in terms of pharmacology and metabolism, our half-life is about 8 or 9 hours. It actually could support a once-a-day dosing just to throw sort of a critical factor back in there. But I think there's a reason to believe that once a day, regardless of sensitivity in RCC patients, et cetera, but from a pharmacokinetic perspective, I think our half-life is sufficient to support once a day if it's going to work.

Good. So we'll wrap it up for the people that have to go. We're all going to be around to 1. And so if the team could migrate over towards lunch, couple of other logistical things. We did bring Trevi a lot of water bottles, would love you guys to be advertisers for us. And we just really appreciate everybody that showed up in person. So thank you.

Good afternoon and welcome to the Trevi Therapeutics First Quarter 2026 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

Various remarks that management makes during this conference call about the companys future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K, which the company filed with the SEC on March 17, 2026, as updated by our subsequent filings.

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so even if its views change.

I would now like to turn the conference call over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for our first quarter 2026 earnings call and business update. Joining me today on this call are my colleagues, Dr. James Cassella, our Chief Development Officer; Farrell Simon, our Chief Commercial Officer; and David Hastings, our Chief Financial Officer.

Dave and I will make some initial comments, but are going to keep them brief as we have a robust presentation this Thursday at our Investor and Analyst Day. After our comments on the quarter, the team is happy to answer any questions you may have. 2026 is an important year of execution for the company, and the team is focused on delivering. Following our positive FDA meeting in the first quarter to align on our IPF-related chronic cough program, the team has finalized the study protocols for our Phase III trials and has been busy identifying global sites for both pivotal studies. We expect to initiate the first of those 2 studies this quarter, followed by the second study in the second half of this year.

After gaining alignment with the FDA in our end of Phase II meeting, we now intend to submit a meeting request and protocol to the FDA to discuss our non-IPF interstitial lung disease or non-IPF-ILD-reated chronic cough program. We intend to propose an adaptive Phase II/III study to confirm dose and powering assumptions in the Phase II study prior to rolling into 1 pivotal Phase III study for approval. If all goes as proposed to the FDA, we expect to initiate this trial in the second half of the year. This non-IPF-ILD population will mimic the patient profile of patients in our IPF trial as it will include patients who have established lung fibrosis and chronic cough.

There are a lot of synergies with our IPF studies as these patients with non-IPF-ILD are seen in the same care centers by the same pulmonologists. So as we negotiate CDAs, contracts and budgets for the initiation of our IPF-related chronic cough trials, we have this trial in the scope so that we can act quickly once we have alignment with the FDA on the protocol.

Finally, for refractory chronic cough, we also expect to initiate a Phase IIb parallel arm dose-ranging trial with 3 doses and placebo this quarter as well. The protocol is finalized and has been submitted to regulatory authorities, and we are actively qualifying sites for this trial. This trial includes a sample size reestimation or SSRE, which will read out when 50% of the patients complete the trial and is in place to confirm powering assumptions and adjust the sample size if necessary. We expect the SSRE readout in the fourth quarter of this year.

One final update I would like to give is on the advancement of our intellectual property portfolio. We own the worldwide rights for our drug and are acutely focused on prosecuting incremental patent coverage in addition to the patents that have already been issued. This quarter, we had our core method of treatment patent issued for IPF-related chronic cough in Europe as well. This patent had already been issued in the U.S. and provides protection through 2039. We filed additional applications this year in the U.S., which, if issued, would extend the patent coverage through 2046. We will keep you updated as incremental IP evolves.

Before I close, I want to note there are 2 important meetings this month where we hope to see many of you. The first is our Investor and Analyst Day this Thursday, May 7, from 10:00 a.m. to 12:00 p.m. Eastern Time, followed by an optional lunch in New York City. At this event, we plan to lay out details for the next clinical trials, the projected time lines for each of our chronic cough programs and discuss incremental data we have developed as we continue to analyze our existing clinical trial data. We also will share commercial learnings based on recent market research and hear from KOLs on their perspective. So it should be an informative event. We will post the webcast and slides after the event for those of you that are unable to join us.

Second, we will also be very active at the American Thoracic Society or ATS meeting this year, with all 6 of our submissions being accepted for either presentations or posters. We will also be holding an investor analyst event at ATS, where Jim and Dr. Philip Molyneaux, the lead investigator on our CORAL trial, will summarize and share the various data being presented at the conference. This event will be a lunch meeting being held on Monday, May 18. If you plan to attend ATS, please reach out to us as we would love to have you join.

In closing, we are focused on executing against our plan of becoming the leader in chronic cough, providing therapy for these patients where there are no good options and in the process, creating meaningful value for patients and our shareholders. I will now turn it over to Dave for his remarks, and then we are happy to answer your questions. Dave?

Thanks, Jennifer, and good afternoon, everybody. My brief remarks today will focus on our most important financial metric, which is our cash position and the runway it provides. We ended the first quarter of 2026 with approximately $172 million in cash, cash equivalents and marketable securities. This balance does not include the $162 million in net proceeds from our underwritten common stock offering completed in April 2026. The offering was well received, and we appreciated the strong support and participation we got from our current shareholders, and we are grateful that we were able to attract new investors to Trevi.

Additionally, with the completion of this offering, we accomplished 2 major objectives. One, we removed any financial overhang when we reached critical high-value clinical endpoints; and two, we extended our cash runway into 2030. Included in this runway guidance is the funding of our development program in patients with IPF-related chronic cough potentially through FDA approval. And we also expect these cash resources will enable the company to fund and report top line data from the planned Phase IIb clinical trial and potentially a subsequent Phase III trial for the treatment of patients with non-IPF-ILD-reated chronic cough, and it funds the planned Phase IIb trial for the treatment of patients with RCC.

Our planned spending of these resources also include pre-commercial activities but does not include any expenses related to the commercial launch of Haduvio or any other clinical trials. So with that, I believe we are now well positioned to execute our clinical trials with funding through critical value inflection points. Operator, we can now open the call for questions.

[Operator Instructions] Our first question comes from the line of Roanna Ruiz of Leerink Partners.

A couple for me. First one, I was curious, what is your goal for the upcoming meeting with the FDA to talk about the protocol for your Phase IIb in non-IPF-ILD chronic cough? And if you could elaborate like anything you expect that might be up for discussion with the FDA versus more straightforward questions?

Roanna, this is Jim. Thanks for the question. So basically, that meeting is designed to discuss our intention for the ILD program. We will be submitting the full Phase IIb/III protocol with that for discussion and really talk about our intentions on using that in an sNDA strategy so that we would support approval with that adaptive Phase II/III design. So there's going to be details about our patient population, how we're going to use the Phase II for our dose selection, confirmation and defining the dose for going into Phase III and then pulling up the results from the Phase II part of that study with the interim analysis to confirm our power assumptions and for the Phase III component.

Makes sense. And then a quick follow-up. Thinking about RCC Phase IIb potentially ramping up as well and moving forward in non-IPF-ILD. Could you talk a bit about how you plan to balance resources and prioritize things as you have many really interesting things going on and moving forward?

Yes. It's -- we don't like a lot of sleep. We have things under control. I -- this is not my first time running multiple programs with a small team. We use our internal expertise. We have leveraged very experienced CRO, one that I've worked with from my last NDA, have a lot of years of experience with them.

So it's a really tight team. Our vendors that we selected are really here to support us across all of our programs. So I think we're in a good position to be able to do these things. I have no questions that we have the capabilities and the intellectual horsepower to get these things done. And we have been working with [ small and ] small companies for almost 40 years now. We know how to manage the resources to get these things done.

I would add to, Jim, Roanna, we have added probably 10 people in the last -- since getting our Phase IIb results. We added a really experienced pulmonologist. We've added several clinical people. So 10 people for us is a lot of hiring. And so we have tried to scale appropriately to address the business of these trials.

Our next question comes from the line of Judah Frommer of Morgan Stanley.

Two for us. I guess, just from a competitive standpoint in RCC, we have a P2X3 readout coming midyear. Just curious how you think the landscape evolves for Haduvio kind of along the spectrum of possible outcomes for that P2X3 readout. I guess, if results are unexpectedly strong, what does that do for your opportunity in RCC? What does it do maybe for enrollment in the RCC trial?

Farrell, why don't you answer the competitive landscape and Jim can talk about enrollment?

Yes, Judah, thank you for the question. When we look at the competitive landscape, especially Camlipixant, which we'll be reading out soon in the next couple of weeks, we're hoping that they are successful here, right? This is a large unmet need patient population with no approved therapies and definitely a category that can support multiple modalities. We have strong differentiation with our central and peripheral mechanism of action. And I think what we'll take you through on Thursday in the Investor Day is exactly how that positions us for success.

I'll turn it over. I'll just say, on the flip side, if Camlipixant is unsuccessful in that space, I think we'll have to take a look at what is our competitive positioning, but we have a really strong efficacy and see what the Phase IIb results say and see what the commercial opportunity lies ahead. But it's still a large unmet need patients are waiting for us. And I'll turn it to Jim.

Yes. On the enrollment side, we have our investigators signed up for that study. There's a lot of excitement. There's a lot of patients available to us. Irregardless of what happens in that environment, we're strongly supported by the investigators that we have for the study who really talk about a lot of patients being available and interested in being in our study. I think our different mechanism, the data that we've shown, the strength of the data that we have out there still is really the absolute driving force for the interest in being in our study.

And [ R2b ] will be done by the time they ever got approval. So it might be a Phase III issue to deal with. But yes, thanks for the question.

Great. And then just maybe more high-level philosophical just on the ILDs with kind of more inhaled formulation drugs kind of entering or late stage in kind of the IPF and PPF space, right? A common AE in a lot of those trials is cough. So just curious how you think the opportunity for Haduvio could be impacted by maybe more inhaled therapeutics in the PF space.

We get this question a lot. I think, obviously, we're treating more of a chronic cough that's more systemic. Now whether the hypersensitization intertwined with them taking these inhaled products and you might be able to settle that down, that's something that's going to have to be learned over time.

I do think these different therapies are helpful. They'll define the market. They create options, but we can lay alongside all of these. That's why Jim has been busy doing these DDI studies. But whether we can sort of help with the cough due to their delivery system, I think that will have to be discovered.

Our next question comes from the line of Alexa Deemer of Cantor Fitzgerald.

Congrats on the great quarter. So for the guidance for the data readouts for the upcoming program, so this begins in the second half of 2027. And I just wanted to ask if there are any other data updates planned we can expect before that?

Yes. I mean we have the SSRE, the sample size reestimation, at the halfway point of the RCC trial. We should get that in by the fourth quarter of this year. We'll have to see how enrollment unfolds, but that's what we're working towards. So that's a pretty insightful readout on the RCC trial, I think.

Otherwise, our current plan is second half of '27, but I want to echo what Jim said, I've been going to a lot of these investigator meetings as well. There is a lot of interest and attention on this -- on our programs. So the team is, I think, setting us up for success here. So we'll continue to update you guys as we move through the trials, but we are definitely moving along nicely.

Our next question comes from the line of Serge Belanger of Needham & Company.

This is John on for Serge today. So just a couple from us. First, I might be jumping the gun here a little bit, but on the SSRE and RCC coming up later this year. Curious what some of the key checkpoints will be that you're looking for during this analysis. I would imagine it might look somewhat similar to the IPF one done during Phase II. And in the event of requiring additional patients, just curious how you might expect that to look?

And then secondly, on the IP front, I believe you have patents issued through 2039. Curious if and where you'd look to expand that portfolio ahead of the potential commercialization of Haduvio.

Yes. Jim, do you want to do the SSRE?

So the SSRE is exactly what we did with CORAL. It will be at the halfway point, looking for conditional power of 80%. If the numbers are below that, if the conditional power at that point is below 80%, we will upsize proportionately. And like we had in the CORAL design, if there's futility, it will be recognized too. That's going to be down in that 30%, 40% range. So I think conditional power. So it's really what you expected from CORAL is going to be carried over to here, and we'll be reporting whether or not we have to stay the same or upsize.

Yes. And your second question, John, about IP. So -- we are in an interesting position now. We've got the [indiscernible] base core patents issued in IPF. And now we're also -- we have a good view of what our label is going to look like. So now we are starting to prosecute the different sort of label enablement patents. So things that we're zeroing in on the label, like the final titration schedule, like how you dose adjust it with food or hepatic impairment. Jim is running a lot of different Phase I studies. Those tend to be quite rich for IP.

So our goal at this point, now that we've got a nice broad sort of method of treatment patent around treating cough in these indications, now we'll start building around the label. We'll keep patent applications open. So as we complete development work and learn new things, we're able to file incremental IP around them. So our goal would be when this drug actually launches that we've got multiple patents around the original base patent.

Our next question comes from the line of Ryan Deschner of Raymond James.

You have some very interesting dyspnea data coming up at ATS later this month in Orlando. How impactful do you think dyspnea is as a quality of life metric for IPF chronic cough patients? And how relevant is potential modulation of dyspnea for the RCC and non-IPF-ILD indications? And I have a follow-up.

Yes, Ryan, this is Farrell. Thank you for the question. We've actually done a lot of research with physicians and with payers around this point. When you look at the top 3 most common complaints from these patients, whether it's IPF or ILD, dyspnea is in that top 3. It's cough, dyspnea and fatigue at the top 3. So it doesn't change our commercial thesis, but what it can do is definitely complement the speed of uptake of the product and also, I think, just the adoption from patients because it's going to be helping them across more than one of the experiences that they have at [ Impax ].

And payer conversations, right?

And payer conversations, it will help in payer conversations. It will help justify additional value.

Got it. And then how do you plan to try to minimize placebo in the RCC clinical program? And if high potential placebo is much of a concern in the IPF chronic cough and non-IPF-ILD indications?

Ryan, it's Jim. So I think we have solid data from our CORAL study in the IPF population, came in with under 20% placebo response. I think that was expected. I also think that, that's probably in the world of chronic cough, that's probably one of the more well-behaved populations and expect to see something like that going forward. I think there's precedent here in the RCC world that the placebo response could be a little bit more variable and a little bit more ranging. We are doing everything in this trial to really control for things that can contribute to a placebo response.

I think a lot of it is having an extremely well-controlled trial. So we're doing our best there. I think we are incorporating at the advice of some of the experts in the RCC space, a placebo run-in period to try to mitigate any of the response there. The idea there is to look for stability around lower end of cough response. So we are incorporating those things. And of course, just sort of the rules of thumbs that I'm bringing in from my CNS background where placebo response is always a big concern is really about trial conduct and making sure that you don't set false expectations that you don't overpromise and things like that, that can help contribute to the overall placebo response.

Our next question comes from the line of Debanjana Chatterjee of Jones.

Congrats on all the progress. So looking forward to ATS, what are some of the most exciting developments we should look forward to? And I have a quick follow-up.

Jim and I will both be there. We're looking at each other. Jim, you go ahead and hear the offer on a bunch of them.

So, it's -- I think we have some exciting updates in the oral presentation that will be given by Dr. Philip Molyneaux. I mean that's going to be some new sub-analyses from our CORAL study. I think there's also going to be some interesting presentations and posters on cost-outs, our analysis of the cost-outs were both CORAL and RIVER. And it was brought up earlier, but I think our breathlessness data being presented by Don Mahler, who is really one of the key experts in this space is really going to be exciting poster to get out that initial analysis that really shows some benefit here on the breathlessness piece of things. So I think those are highlights. I think that really add some new information into the data flow for us.

Appreciate the color. And just a quick follow-up. So I know, of course, FVC is not an endpoint that you are pursuing. But like given that you'll be following the IPF patients like 52 weeks at least, right, in the Phase III program, do you expect to see some trends there? And even if that's kind of like a safety endpoint?

So we are following FVC. We have it at baseline. We have it throughout the 52-week time period. We will be able to look to see what's there. Our ends are very different than what you would expect from an IPF trial because FVC is highly variable, and I think that drives the size of those trials. But all I can promise you is that we will see what we see and report it out.

Our next question comes from the line of William Wood of B. Riley Securities.

Congrats on a nice quarter. So just curious when we're thinking about the peers P2X3 readout coming up. I was curious if there's anything specific that you might be looking for in that trial regardless of whether it's positive or negative in terms of taking forward to the FDA that you think they could really improve your learnings on your own trials?

I mean I'm just going to jump in, Jim, you add any color. Thanks for the question, William. I don't think so. P2X3s have had to kind of chase this path of the highest level of coughers and placebo run-ins and highly adjudicate the indication. We've shown data that our drug works broadly in IPF chronic cough and refractory chronic cough across different cough counts. So I think that we have to be a lot less fussy with who goes into the trial and how we get results. We'll obviously be interested in the placebo effect and how they've controlled that. But those trials were upsized.

The bigger trial was upsized twice, and that's always tricky. I think they're also managing a much tighter response. So we'll look at it. We're interested. I agree with Farrell. I hope they see some results for patients. but they are guiding towards about a 15% to 20% placebo-adjusted change in their calls. We would expect much better performance of our drug. So we really are looking to be best-in-class and the most refractory patients for our drug. So it's more, as Farrell mentioned, just how we position the drug and where we go. But I would say nothing that really impacts our program. We'll learn more from our Phase IIb than we'll probably learn from their Phase III data.

Got it. That's helpful. And then one brief quick add-on. Just in terms of sort of setting our expectations for the -- for your KOL event coming up as well as at ATS, is there anything specific that the FDA may be looking for in terms of guiding for your non-IPF-ILD-related chronic cough trials that you may be highlighting at these really sort of bolster moving into this and/or certain subsets of populations as you look to meet with them in the second half.

Well, we are having an ILD expert in the U.S., Dr. Toby Maher, who runs a big ILD center. He's going to speak there. He's got to join us by Zoom because he has clinic. But one of the topics we've asked him to cover is why in his judgment, an IPF and an ILD patient is the same or not the same as it relates to cough. So you'll hear straight from one of the experts here. Toby has been involved in our program from the beginning. He knows our drug quite well. He actually sat on our FDA call with us. So you'll get some independent insights from really one of the leading voices in the ILD space on Thursday.

[Operator Instructions] our next question comes from the line of Kaveri Pohlman of Clear Street.

Just like a follow-up on the previous comments you made on the Phase IIb RCC trial design. I was wondering how you are thinking about enrolling a truly addressable patient population to fully derisk the program, particularly given the expectations that many of patients may be P2X3 antagonist experience in real world. And broadly, just like on a high level, there appears to be an increasing focus on the development progress in IPF and non-IPF-ILD. Obviously, alongside continued efforts in RCC. How do you think about the relative opportunity across these indications in the context of the evolving treatment landscape? And what key challenges in RCC will need to be addressed to fully realize its potential?

There were a lot of questions there to disentangle. So I'll just kind of start from a strategy perspective. Trevi has always been led as an IPF sort of and then adding an ILD-led strategy, primarily because of our commercial strategy, specialty, high pricing, specialty sales force. So that was always our focus. I think as the RCC competitive landscape sort of fell away and really there wasn't much left, some of the experts came to us asking us to please try our drug in RCC, we did and got very strong data. So I think definitely a commitment to RCC, but it is sort of the third leg of the stool here. With regard to the variability in the program and P2X3 responders, anything, Jim, on that?

I think are you asking there's going to be people who have experienced with P2X3 that may be entering our trial. I mean, I think the key there is if they meet the eligibility requirements and they've been off their P2X3 for an appropriate period of time, they still have the requirements to get into the study, they're fair game for coming in.

I mean we want people with various experiences. We know this is a refractory condition, and people have tried a lot of different things. And they may or may not have succeeded on a P2X3, but if they meet our entry criteria, they'll be coming into the trial. So I don't think it really differentiates from any other type of therapy that they've tried in the past. They will meet the eligibility requirements for being off of the P2X3 for a certain amount of time.

I am showing no further questions at this time. This concludes our question-and-answer session. I would now like to turn the conference back to Jennifer Good for closing remarks.

We appreciate you joining us for today's call and look forward to hopefully seeing many of you later this week and this month. Thank you.

This concludes today's conference call. Thank you for attending. You may now disconnect.

Good afternoon, and welcome to the Trevi Therapeutics Fourth Quarter and Year-End 2025 Earnings Conference Call.

[Operator Instructions] Please be advised that today's conference is being recorded.

Various remarks that management makes during this conference call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K, which the company filed with the SEC this afternoon.

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so even if its views change.

I would now like to turn the conference call over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for our fourth quarter 2025 earnings call and business update. Joining me today on this call are my colleagues, Dr. James Cassella, our Chief Development Officer; Farrell Simon, our Chief Commercial Officer; and David Hastings, our Chief Financial Officer. I want to welcome Dave to his first official earnings call with Trevi. His experience has already been felt in the company, and we feel very fortunate that we were able to add him to our leadership team at this important time of execution and growth. So welcome, Dave.

I will make some comments on the business, and Dave will make some brief financial remarks. Then the team is happy to answer any questions you may have. 2025 was a major inflection point for growth at Trevi, driven by our positive data readouts in both the CORAL trial in patients with idiopathic pulmonary fibrosis or IPF related chronic cost and the RIVER trial in patients with refractory chronic cough or RCC. As a result of these data, we were able to raise capital, setting us up nicely for the next round of trials for each of our indications. That momentum has carried into the early part of this year as we have been preparing to initiate the next set of clinical trials. This work recently culminated in a positive end of Phase II meeting with the FDA for our IPF-related cough program. We believe the path forward for our registration trials is clear, and the team at Trevi has been moving aggressively to initiate our Phase III program.

Let me provide you with an update on where we stand in each of our chronic crop indications. Beginning with our lead indication of Haduvio for the treatment of IPF-related chronic cough, at our recently held end of Phase II meeting with the FDA, we believe we gained overall alignment on the plan for the remaining development program and pathway to NDA. First, I want to share that the meeting was very collaborative and we were appreciative of the preparation and comments from the FDA, especially with all of the changes going on at the agency. We had constructive dialogue around each of our questions and left with a good understanding of the path forward.

During our interaction, we confirm the primary endpoint using the objective cough monitor and discuss the proposed key secondary endpoints and the evaluation of these end points. Based on the FDA's input, the company plans to conduct 2 pivotal Phase III clinical trials and obtained agreement on the remaining Phase I clinical studies to support an NDA submission. The company plans to conduct these 2 Phase III trials in parallel and is on track to initiate the clinical program. We plan to initiate the first trial in the second quarter of this year. This trial will be a global 52-week trial with a primary efficacy endpoint following 24 weeks of fixed dosing. We have planned for the trial to include approximately 300 patients.

The second confirmatory Phase III trial, which we expect to initiate in the second half of this year will also be a global trial with a primary efficacy endpoint at 12 weeks and is estimated to enroll approximately 130 patients. The 2 studies are almost identical in design, except for the different duration for the primary efficacy endpoints and sample sizes. The reason for these differences is the FDA interest in a 24-week readout to support durability of effect in at least 1 of the trials. As for the end of the trials, the 52-week trial with the 24-week endpoint is powered for all of the key secondary endpoints that we would hope to include in the label and supports an adequate safety database.

The second Phase III trial is studying a 12-week endpoint to confirm the primary efficacy outcomes along with providing additional safety through 12 weeks of dosing. IPF-related chronic cough is a new indication for the FDA, and we believe this pivotal program provides robust safety and efficacy data for a potential NDA submission. In the U.S., there are approximately 150,000 IPF patients, 2/3 of which have uncontrolled chronic cough. These cough patients have a high unmet need with no FDA-approved therapies. With our distinct mechanism of action and known safety and tolerability profile, we believe we are well positioned to have potentially the first therapy for the treatment of IPF-related chronic cough.

Also a quick comment on the remaining Phase I studies. These are all standard label-enabling studies, which we had already been planning for in our development program, and we're aligned with what we had submitted to the FDA in our briefing document. Jim can give more color in Q&A if you are interested.

Following alignment with the FDA on our IPF-related chronic cough program, we now intend to submit a meeting request and protocol to the FDA to request our non-IPF interstitial lung disease or non-IPF ILD-related chronic cough program. We intend to propose an adaptive Phase IIb trial to confirm dose and powering assumptions prior to rolling into 1 pivotal Phase III trial for approval. We are planning to file a supplemental NDA for this indication. We are planning to have this meeting in the third quarter of this year, and if all goes as planned with the FDA, initiate that trial by year-end. This population will include non-IPF ILD patients who suffer from lung fibrosis and chronic cough. We estimate there are approximately 228,000 non-IPF ILD patients with 50% to 60% having uncontrolled costs. This more than doubles the market opportunity of IPF chronic cough, and these patients are primarily seen by the same pulmonologists at CIPF patients. This keeps our clinical and commercial efforts efficient and create synergies.

Finally, for refractory chronic cough. We are planning to conduct a Phase IIb parallel arm dose-ranging trial with 3 doses and placebo. The protocol is drafted and being submitted to regulatory authorities, and we have selected sites to conduct this trial. This trial is interesting scientifically as we explore whether dosing in RCC patients is lower or equivalent to doses we are testing in the IPF chronic cough trial. We plan to initiate this trial in the second quarter of this year as well and have included a sample size reestimation readout when 50% of the patients complete the trial.

It has been a busy time at Trevi preparing to launch this next round of clinical trials. Jim and his team have been working very hard to leverage the important learnings and relationships we have already built as well as to expand our clinical footprint into the U.S. We are excited to initiate these trials and begin enrolling patients.

Before I close, I want to note there will be 2 important meetings we are preparing for in the second quarter where we hope to see many of you. The first is an in-person Investor and Analyst Day on May 7 from 10:00 a.m. to 12:00 p.m. followed by an optional lunch in New York City to discuss the company's clinical and commercial strategy. We will be joined by both IPF and RCC KOLs. At this event, we plan to lay out clinical trials and time lines in more detail, share recent commercial learnings at Farrell has been busy at work on based on our recent data here from KOLs on their perspective, and I also plan to discuss our active efforts around obtaining additional intellectual property. So it should be an informative event.

We will also webcast the event live for those of you that can't join us in person. Second, we will also be very active at the American Thoracic Society, or ATS meeting this year with all of our submissions being accepted for either presentations or posters. We will be sharing some new data from our various trials at this meeting. We are planning on holding an investor event at ATS, where Jim and Dr. Philip Malone, the lead investigator on our CORAL trial, will summarize and share the various data being presented at the conference. This meeting is being held in Orlando from May 17 to 19, with our ATS investor event being held on Monday, May 18. If you plan to attend ATS, please reach out to us as we would love to have you join us.

So in closing, Trevi is well positioned to execute against our plan of becoming the leader in chronic cough, providing therapy for these patients where there are not good options and in the process, creating meaningful value for our shareholders.

I will now turn it over to Dave for his remarks, and then we are happy to answer your questions. Dave?

Thanks, Jennifer, and good afternoon, everybody. First, I just want to say I'm thrilled to be participating in my first earnings call as CFO of Trevi. And before moving to the financial results, I want to take a moment to talk about why I took this role. The company has impressive clinical data in indications of high unmet medical need that offer a significant commercial opportunity. Importantly, given their specialty nature, we can commercially launch our indications effectively. In addition, the company has a proven track record of using its capital efficiently as it progresses with its key clinical programs. Also, after meeting the team, I felt confident in their ability to execute and I'm excited about the opportunity to contribute.

Now turning to our key financial metrics, which are cash or way and what that runway funds. We ended 2025 with approximately $188 million in cash, cash equivalents and marketable securities, which gives us an expected runway into 2028. This runway allows us to provide top line data in our key clinical trials. This includes our Phase IIb clinical trial in RCC our Phase IIb clinical trial in non-IPF related chronic cough and importantly, top line data in our 12-week pivotal Phase III clinical trial in IPF-related chronic costs. So while we're well positioned from a cash runway perspective to reach key clinical milestones, it is important to ensure that Trevi is always appropriately capitalized given the key inflection points and significant clinical trial data readouts the company has in front of us.

So with that, I'll now turn the call back over to the operator to open the call for Q&A. Operator?

[Operator Instructions] And our first question comes from Roanna Ruiz with Leerink Partners.

A couple for me. I wanted to check on the remaining Phase I studies that you talked about with the FDA at the end meeting. Could you elaborate a bit on what questions they're meant to answer and how efficiently you think you can complete them in the near term?

Ron, this is Jim. Thanks for the question. So these are pretty much label informative studies. So specifically, the FDA has asked us to look at NeurodomaLast as a newly approved antifibrotic agent to see if there's any drug-drug interaction with that, we had previously done that with pirfenidone and tentative. So we were kind of expecting this 1 is it going to be coming along. The idea there is to make sure that there's no PK drug interaction that could affect the PK levels of either NeurodomaLast or vice versa, the PK of on [indiscernible]. So that's the first one. That was kind of expected given that we just completed those other ones.

The other 1 was related to our mechanism of drug metabolism. We are metabolized in part by cytochrome P450 liver enzymes, specifically, were metabolized by Cytochromes P450, the 2C9 and 2C19 isoforms, we had planned on doing an inhibitor study to look at drugs that inhibit the enzymes to see if the effect. If it affects RPK, the FDA wanted to just step 1 more step further and look at inducers of those enzymes. So again, it's kind of routine, we'll be able to inform on the physicians through the label and what happens when we do that. Now what we had also proposed and was accepted was standard label-enabling studies on renal impairment, hepatic impairment, food effect and things like that.

So in a good place there. I think we have a very good idea of what we're required to do for the pathway to the NDA. These are not rate limiting in any way. They can be done in parallel with the Phase III, and we'll be performing those as we go along.

Great. That's helpful. And a separate question on non-IPF ILD and talking about the -- going in front of the FDA about that trial design as well. Any design features that you particularly want to align with the FDA most? And is there anything that you expect maybe some questions or things you may have to have more of a discussion about with the FDA on? .

Yes, great question. I think the beauty of our timing here is that we're coming off of a very positive end of Phase II meeting in IPF. And you know is a form of ILD, interstitial lung disease. So we're really looking at the other part of that ILD population. So I think a lot of the learnings that we have from the end of Phase II meeting directly relate to what we're looking to do in the non-IPF ILD. So everything we learned in the end of Phase II meeting in terms of study design, what the FDA is looking at for study duration, even our endpoints really will carry over. So what we want to do with that meeting is really introduce them to the concept that we're interested in this other part of the population. We are looking at doing this in terms of a Phase II, Phase III adaptive design, as Jen mentioned, the Phase II part is really -- this is a slightly different population. There will be other comorbidities associated with this non-IPF ILD population.

So we're going to do some dose ranging in the Phase II part. The idea of the adaptive design is that we were able to pick our doses, determine what our effect size is, look at the variability in this population, immediately translate that into the Phase III study. There will be a data readout in between there. So we're basically going to lay out that concept with them in the Type C meeting that we plan on having with them.

Our next question comes from Judah Frommer with Morgan Stanley.

Congrats on the progress. Dave, congrats on joining the team. I guess maybe just first from us on non-IPF ID. Was there any conversation in the end of Phase II about potentially adding an arm in the pivotal program for IPF that could include non-IPF patients if not, did you feel that it just wasn't the right format. And also in the end of Phase II, can you help us with any color on discussion of 1 trial versus 2? I know you had always assumed that you'd be doing 2 trials here. But was there any discussion around that?

Yes. So in terms of non-IPF ILD -- we -- the IPF program is our lead program. It has a very clear directive. It's a very distinct population. It's what we had actually talked about when we filed our IND. So we really kept it to the IPS part of the ILD population. The idea was that we would take the learnings from that meeting and then apply it to the ILD. So we did not have any direct conversations about that.

I'll let Jen chime in on the second part .

Yes. The 1 versus 2, Judah, I think we got good comments from the agency and had good dialogue with them in the meeting. As you know, there's sort of this in between phase now where there's this New England Journal articles floating around that hasn't really translated down into FDA guidance. I think that causes a little bit of wondering what to do with that at FDA, especially for us because it's a brand-new indication, a chronic cough drug has not been approved, and this will be our first indication approved. So as our management team stepped away from everything we heard, we made the decision that it was best to really lean in on our lead indication here and conduct a robust trial so that we didn't get caught sort of in any kind of changes around view there. So it was really a decision we made as a company.

There's a lot of confidence that we can run a successful study and these are not big trials because of our drug effect size. So I would say it was sort of room to move, probably either way there and we opted to protect our lead program and move forward with 2 studies.

That makes sense. And then just 1 on refractory chronic off. It sounds like you have a plan there. Just curious, I guess, on any read-through you'll be looking for in the P2X3 readout kind of around midyear and if that could impact the program?

So it's interesting. That should read out in the third quarter. Obviously, important for patients. I do think our strategy is a bit different. We're going after treatment failure patients. The only read through there, I think probably particularly Jim will be interested in is kind of what did their placebo effect look like. I think we hope the trial works sort of work or not work. I don't think it really impacts what we're doing. We will look at some of the trial details. I don't know that those will all be available in the third quarter. It may come later as they publish the data. But that's probably the most interesting thing.

I don't know, Farrell, Jim, anything you'd add? No.

No, I think that's right.

Next question comes from Annabel Samimy with Stifel. .

This is Jaya on for Annabel. Congrats on the progress. I had 2 questions. The first 1 is just related to cash runway. It is sufficient for Phase IIb in RCC, the Phase IIb P and a 12-week readout of IPCC. Does that mean 24-week data covered 4-week IPCC?

Yes. So that's correct. This will get us through, obviously, those key clinical milestones you outlined. And as I mentioned, look, it's important that the company is always appropriately capitalized and we'll make sure that the funding will be there for all our key clinical studies.

And Dave, can I just add 1 thing from history because I've been around this. I think what changed here fundamentally from our FDA meeting is that the FDA wants 52 weeks of controlled safety. So we have to keep our placebo arm on and placebo for 52 weeks, which means we can't read out that 24-week end point. until the end. So that's been a little bit of shift in the requirement. If we could read it out at 24 weeks, we would be able to cover all this. But now that we got to leave that study blind didn't go all the way to the end, that's where a little bit of the cap shows up. Having said all that, we're still nailing down exactly the non-IPF ILD plan and all that.

Yes. Also, I'd just like to add, I mean, strategically, we could deploy cash differently, right? But I think expanding indications is important as well. So that's why getting the non-IPF ILD study going and getting data there is also very important.

My other question was regarding secondary endpoints in the IPF pivotal trial. What are you guys thinking? Or is there any color you can give there?

Sure. This is Jim. So it's very important in this program that we get the patient perspective. The primary endpoint is objective cost monitor. Of course, we use the same thing in the CORAL study, but also some of the PROs that we developed and used in the CORAL study will be bringing forward into the Phase III program. These are primarily a around patient perception of cost frequency, cost severity. We also had some very interesting data that came out of the CORAL study in terms of potential impact on subject perception of breathlessness, and so we are moving that up into a key secondary category because we have some very interesting findings there. And of course, it's a very important measure because patients do feel breathless after these coughing period. So we think that's a very important endpoint. It's something that the patients are very concerned about.

And Jim, that's one of the things we'll share at ATS.

Yes, we have some great data to share at ATS. So spilling the beans a little bit.

Just only to a little bit.

Our next question comes from Alexa [indiscernible] with Cantor Fitzgerald.

Congrats on the great year. This is Alexa on for Josh. So 2 quick questions from me. The first being, do you expect the label dose in RCC to be the same as in IPF? And if not, do you expect to procure additional IP for dosing in RCC.

And then the last question I have is, do you plan on sharing data from the RCC study this year?

Yes. So I'll take that on Alexa, by the way. So the label dose, that's part of what Jim's mission is. He's going to go off and figure that out. When you look at the crossover data, it appears that, that whole effect is there at the lowest dose, very early. And in by 1 week, the first time we measured it. I think there's sort of a mechanistic reason of why that may be true that you need less drug. And so Jim is going to be really the lower end of that dose range along with the QD dose we're going to look at actually. So we've sort of told Jim, once he figures out what's the appropriate dose, we'll figure out the strategy.

And if we do end up below this dose range we're in now, there will be additional IP because there will probably be some new formulation work that needs to be done, which we're actually working on in parallel. So that was good. Your second question, I'm sorry, what was that?

Just if you plan on sharing data from the RCC study?

Yes. Sorry, I didn't -- I only wrote the as part of that, and then I couldn't remember what that meant. Yes. So we have built in the sample size reestimation. We won't get all the way to the end of the RCC trial this year. We are targeting getting to that sample size reestimation readout by later this year. So we will hope to do that. When we initiate the study formally, we'll lay out guidance for both -- for that milestone as well as the full trial readout.

Our next question comes from Serge Belanger with Needham.

So a follow-up regarding the secondary endpoints. I think in your prepared comments, you mentioned the larger of the Phase III studies was powered to further with secondary endpoints to be included in the label. Just curious if that was an FDA request or it's a strategic decision by the company. And second question, just whether there was any discussion at the end of Phase II meeting regarding orphan drug designation or that's a conversation that takes place separately at a later time.

Go ahead, Jim.

I'll take the first part of that question. So it's really a strategic question, Serge, because the FDA is looking for 52 weeks of controlled data, safety data. And in that study because it has to run longer, it's most efficient that we sort of build in a little bit more into that study. So obviously, that's a study that our 24-week primary endpoint of fixed dosing. And also because we have -- we will meet our basically, our safety database requirement for the 52 weeks on drug, it was easier and more efficient to build in all of our key secondary endpoints. Remember, I mentioned these are PROs. So they're not quite as clean as signal. They have a little bit more variability, and a little bit more end to the study. It was most efficient to build all that into the larger Phase III study. And then the second study is really just confirmatory with the 12-week end point. So it's really a matter of efficiency and strategy that we did it that way.

Jim, we proposed that FDA didn't make us do it, right? This is our proposal search, and they agree with it. As far as the orphan drug question, it's a good question. We are going to file this year an application for orphan drug. As you've heard me say before, I'm skeptical whether we'll be able to get it because we're -- while IPF is orphan, we are looking at chronic P, which is largely viewed as 1 of the most difficult chronic cost conditions. So they're probably going to look at that and realize that if it works in IPF chronic cough, it could work more broadly, that's a question we want to answer. I don't want to assume that.

So we will file, we'll ask the question. We wanted to get aligned with the FDA on our program first. So now that we've done that, we'll work to submit that application and get an answer to that question.

[Operator Instructions] Our next question comes from Ryan Deschner with Raymond James.

You had any recent feedback since your big 2025 data readouts from either patients or physicians suggesting increased awareness of ADUVIO or your programs in general which might be able to inform on expectations for enrollment demand for the IPF chronic cough pivotal study and then I have 1 more question.

Yes, Ryan, this is Farrell. So we've been doing a lot of work over the summer in terms of just understanding physicians' behaviors and key drivers of just liking. And what really comes up to the top of the list is the efficacy that was shown. So we've seen an increase in physician understanding. We've also been really active with the patient advocates in the U.S. and ex U.S. environment so that we understand how we can work with them to better support patients. This all nicely flows into the work that Jim and his team are doing in terms of clinical trial awareness and our team have our sights set on that. But we'll give a lot more details on the insights in the Investor and Analyst Day come May.

Yes. I would say, as you know, Ryan, we are going to be entering the U.S. with these trials. And we've been that group. And while we've hosted receptions, we have a lot of these physicians show up and lobby, Jim and myself are getting entry into that. We've had good response time, right, on all our sites. So there's good awareness of our drug, our program, the unmet need. I think I'm excited about the enrollment curves here. I think we can that.

There's a lot of excitement as we read out to the sites in the U.S. Clearly, very high interest in participating in this drug trial.

Got it. And then maybe quickly from a more general perspective. Are you anticipating meaningful read through your programs regarding the relatively new developments to FDA related to plausible mechanism, increased emphasis on basin trial design or even recent turnover at the department.

I would say no. I mean, that's what the beauty of this, Jim, you chime in. But at the end of the Phase II meeting, we have a very clear path forward, and that's the playbook we're going to execute against. I think fortunately, the division -- or the FDA division director was very active in our meeting. So we know she's bought in and solid with that. There's going to be a lot of churn or there is churn going on in the leadership roles we're not sort of under that branch. So I don't foresee that really affecting what we do because we're going to have our heads down for the next 2 years, executing the plan that was agreed to.

So I don't know, Jim, anything you want to add?

No. Other than -- I think you hit the nail on the head. We work with the division. The vision was very clear on what the expectations are for the approval of a drug for cough, which they were very enthusiastic about. They see the Division Director really talked about the need here and the burden on the patient. So I think that was very clear. We have clear line of sight with this division on what needs to get done. I think that's the most important that we're going to work towards.

Our next question comes from Brandon Folkes with H.C. Wainwright.

Congrats on all the progress. Maybe just 2 for me, if that's all right. How do you think about moving forward into a Phase III in RCC in terms of timing post the Phase IIb? Do you expect to make a decision just in terms of sort of the second indication to market where perhaps post that Phase IIb in RCC, we could see a bigger focus on the non-IPF-ILD as the second indication to market given the commercial overlap and then also the fact that you're probably going to get off-label use in RCC.

So that's not the motivation. I would say, obviously, our lead indication is IPF. And I would say our second indication is ILD because they're attached at the hip. I do think, though, ILD, the non-IPF ILD and RCC are both going to be sNDAs. So they would be fast follow-on. So when IPF got approved, we would look to be in a position to file both of those really very closely together. I think if there was ever a resource issue on time, ILD would get prioritized because we'll be launching into those centers, and it makes a lot of sense with IPF. So yes, I think we think about the priorities internally, it's IPF, ILD, it's sort of close cousin.

RCC, we will move along urgently, though. That is a big unmet need. I think our drug has shown good data there. And there's no reason we can't have that ready to go as soon as our IPF drug gets approved. We believe there's only going to be one Phase III trial to run on the heels of our IIb. So we'll be prepared to keep this moving.

Great. And then secondly, coming back to the Phase II IPF chronic cost, can you just reminder or help us think about what's your thinking on the placebo effect in the longer 24-week duration?

That's a great question. Really that question. I think we -- our CORAL study gave us a really good indication of the placebo response. We had about a 17% placebo response in terms of cough. We saw the response in our subjects come in within the first couple of weeks. And then it was a pretty steady respond over that time for the active drug. Placebo was sort of bouncing around that range. It's a slightly smaller study. I don't think we think about it any differently going forward. I think that we are something that we need to figure out. I think we're sufficiently powered to find out what the effect is but it really isn't unknown at this point, and we're going to find that out both in the 12-week trial and then in the longer trial.

So I think it's a stay tuned. I think we're well powered to handle any perturbations around what that placebo response is. I think our primary endpoint -- our trial is powered over 90% for the primary and the key secondary endpoint. So we built in some safety net there as you would for a Phase III trial. But I think we're going to all find that together.

Our next question comes from Steven Jonathan with Jones.

So sorry if I missed this and you've already clarified, but could you comment on the internal expectations around pace of recruitment and enrollment completion in the Phase III IPSCO trials? And I have a follow-up.

Yes. We have good solid data from our CORAL study to lay out some expectations for recruitment. Given the size of the first Phase III, the larger one, we're expecting that enrollment should be about a year to enroll the trial. We're anticipating something between 80 and 100 sites. So I think with those kinds of parameters, the vast majority of those centers will be focused in the U.S., which I think offers all these excellent care centers where there are large numbers of patients. So I think the 1-year expectation is reasonable for a trial like that.

Okay. So assuming the 1 year to recruit and then you have to follow patients for 52 weeks for safety reasons. So by the time this is potentially approved, there could be other IPF drugs such as United Therapeutics BMS admin that's potentially out there. Will you need to do additional like Phase I drug-drug interaction studies to file?

Depends on when those drugs get approved. Theoretically, we would probably have to do a DDI study to make sure there's no effects on the PK. We do know from the mechanisms, whether or not we expect to see some kind of drug-drug interaction there I think it will be a matter of timing. If we're done with our recruitment phase and we're continuing the running of the study, then obviously, we won't need to bring in any more patients. So I think it's a matter of timing, and we'll see what happens. But it's not a big deal to do a Phase I study DDI study. So I wouldn't see that as a barrier.

Our next question comes from William Wood with B. Riley Securities. .

So 2 for me, 1 upfront. So just thinking about in terms of your ILD study, you've mentioned that you're going to do an adaptive design. And I believe in the past, you've mentioned that you're going to stay away from sarcoidosis. But apart from that, how should we think about how your inclusion criteria could look? And should we really expect that to look into all sort of ILDs, including differential forms of pneumonia, just sort of discuss how we should think about that, if you would. And then I have a follow-up.

Yes. We actually had a very insightful meeting with a group of KOLs last year. And it comes down to that -- the commonality that all these patients have even though they may have different comorbid diseases is that they all have interstitial lung disease to a varying degree. They have a certain amount of scarring, that scarring can get worse over time, and they all have cough, whatever percentage that is. So what we came to was that there wouldn't be any basket-type trial where we're picking them based on the diagnosis that they have to base it on the modified buses that they have and the amount of cost that they have.

So I think it really minimizes it to the core essentials, and we think that the fibrosis is probably leading to the cough anyway. So it really does get to the fundamental issues. Now that doesn't mean we won't have to deal with comorbid conditions and CONMED and things like that. We'll work out those details, but I think that's the essence of the trial.

Got it. Makes sense. And then in terms of -- the FDA is sort of continually evolving. And so I was just curious if there's been any viewpoint change on how they're seeing nalbuphine potentially scheduling or not scheduling and just sort of if there's been any updates and interpretation there?

I would say, William, we provided our human abuse potential study. We provided our data from our respiratory safety study, we had a consult on the meeting from controlled substance staff. It was a very constructive meeting. I would say, I think all of our interpretation FDA is less focused on the molecule because that's already unscheduled and focused on our formulation and whether there is anything unique about it that could change the profile around that. Our data has not showed that. Jim did a really nice job of doing a cut around their various terms. They'll look at the end of the study and there just isn't much there.

So I've been living this ride from the beginning. And I would say I just continue to have stronger and stronger conviction that this drug will stay on schedule. So nothing in the end of Phase II to change that. I would say very relaxed tenor around that generally and clear guidance about what they're interested, which quite honestly, was more around dependence that of addiction.

So I don't know, Jim, anything you want to add?

Yes. No, but that's a good point. I think we laid out for them to plan on how we would pull together the data to support the combination at the NDA time. So there's clearly very good day sets that need to be generated with the guidance of VA and CSS where they put out these terms for adverse events that are related to these abuse terms. But as Jen said, there was a lot of discussion or meaningful discussion around observing whether or not there's physical dependence then withdrawal.

Just for a point of reference, that's a label issue, not a scheduling issue. So again, there's 2 different aspects of this that they're interested in. So not that we expect to see any of that but that would be label as opposed to scheduling.

Our next question comes from Kaveri Polman with Clear Street.

This is Christian. I'm on for Kaveri today. So you've mentioned that the 1-year IPF Phase III safety data set could start to teach shooting about things like this neo, exacerbation, hospitalizations and maybe even lung function trends over time. Will any of those be prespecified analyses and what data would actually change how you think about the label or launch strategy?

Yes. So there's a lot of things that we're going to be tracking. We are seeking approval for cough. I think that's first and foremost. We have to support that label. I think the 1 thing that we mentioned previously is that cost patients really do have concerns about shortness of breath. So we are moving breathlessness into the key secondary endpoint. That's clearly related we are clearly going to be capturing data that would relate to these other things that you're referring to. So we do FECs, we do other things, we'll look at hospitalizations. These are going to be patients living with their disease is a terminal condition.

So we'll be tracking those things as well over the course of the year.

Got it. I appreciate the color. And I just have 1 more regarding Phase III IPF population. You've previously mentioned that you would like the population to be a real world as possible and that it will be like the Phase IIb population but with some broadening efforts. Could you possibly talk about which parts of the patient population you're intentionally broadening into versus the Phase II CORO study?

So there's a lot of carryover from the CORAL study. The CORAL study was really a great study in setting us up for this, not only in terms of dose ranging but in terms of understanding the patient population. So we are broadening that we're making as real world as possible, which is clearly what the FDA wants. There will be patients who are on background antifibrotic medications. That was true in CORAL is going to be true here. we don't have a cough count requirement coming into the trial. That was true in Coral. That is true here.

The FDA actually mentioned that nobody expects to find cough monitors in doctors' offices when the patients are going there. We actually have some more data that will be coming out at ATS that looks at minimum cough levels, and there was an arbitrary cutoff around 10% cost per hour. There was some concern about maybe capping those. We are going to cap the number of costs coming in under 10 cost per hour. That came out of the CORAL study. So we're learning the CORAL study but really it's a very similar population to that study.

Thank you. I'm showing no further questions at this time. This concludes our question-and-answer session. I would now like to turn the conference back to Jennifer Good for any closing remarks.

We appreciate you joining us for today's call. I know for all of you guys, this is getting to the end of your earnings season, so you're tired. We look forward to sharing our continued progress in the second quarter as we initiate clinical trials as well as at our Investor and Analyst Day in May as well as ATS. Thank you.

Thank you. This concludes today's conference call. Thank you for attending. You may now disconnect.

Good afternoon, and welcome to the Trevi Therapeutics Third Quarter 2025 Earnings Conference Call. [Operator Instructions] Please note this event is being recorded.

Various remarks that management makes during this conference call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent quarterly report on Form 10-K, which the company filed with the SEC this afternoon.

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so if its views change.

I would now like to turn the conference over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for our third quarter 2025 earnings call and business update. Joining me today on this call are my colleagues, Dr. James Casella, our Chief Development Officer; and Farrell Simon, our Chief Commercial Officer. I will make some comments on the business and financial results, then the team is happy to answer any questions you may have.

The first half of this year was a major inflection point for Trevi with positive data readouts in both the CORAL trial for chronic cough in patients with idiopathic pulmonary fibrosis, or IPF, and the RIVER trial for patients with refractory chronic cough, or RCC. We recently presented these results at CHEST, and it was great to see the interest from leading thought leaders and community pulmonologists. As a result of these strong data, we were able to raise approximately $115 million in June giving us cash runway into 2028 and an ability to execute on the next clinical studies for each indication. It is an exciting place to be in our journey, and we have not wasted any time in moving forward.

Let me provide a brief update on what the team has been up to in each of our chronic cough indications. We have recently completed a couple of important Phase I studies to advance our IPF cough program. The FDA requested we conduct a drug-drug interaction study looking at any potential PK interactions when nalbuphine ER is co-administered with pirfenidone or nintedanib, which are antifibrotics and the standard of care taken by patients with IPF and other progressive fibrotic diseases.

We recently received the data from this study, and we are pleased that there were no clinically meaningful changes in the pharmacokinetics of any of the drug combinations used in this study. We will publish these data in the future, but we did not see anything that will impact the dosing in our Phase III program.

We also made good progress on our TIDAL study, which is assessing respiratory function and safety of nalbuphine ER in IPF patients. Recall, this is a study requested by the FDA to investigate if there was any potential signs of respiratory depression in patients with IPF following dosing with nalbuphine ER. The IPF patients in the study were housed in clinic for 10 days and given increasing dose of drug while having their oxygen, carbon dioxide levels and respiration rate assessed for periods of time.

A planned review of data by an external safety review committee in a sentinel cohort of patients concluded that there were no safety signals in the study to date. As a result, the committee gave approval to complete enrollment for the study. We will include the available data for both the DDI and respiratory safety studies in the end of Phase II meeting package.

As for the end of Phase II meeting, we expect to request that meeting in the fourth quarter of this year. The key points we are looking to discuss with the FDA are to gain alignment on the Phase III program for chronic cough in patients with IPF, get their input on the Phase III study design and other parameters of the protocol as well as agree upon any other NDA-enabling work which needs to be completed. In parallel, the clinical team has been preparing to initiate the Phase III program in the first half of next year and is busy lining up key vendors and identifying sites for these global studies.

We have also been preparing for a study in other non-IPF interstitial lung diseases, or ILD. This population will include non-IPF-ILD patients that have lung fibrosis and chronic cough. We estimate there are approximately 228,000 of these patients with 50% to 60% having uncontrolled cough. This more than doubles the market opportunity of IPF chronic cough, and these patients are primarily seen by the same pulmonologists that see IPF patients. This keeps our clinical and commercial efforts efficient and create synergies.

We plan to request a meeting with the FDA after we align on the IPF pivotal program to discuss our study design and protocol for this indication as well. Once we have FDA input, we will be prepared to initiate this study.

Finally, we have been working on the next study in refractory chronic cough. We expect that study to be a Phase IIb parallel arm dose-ranging study and are planning to initiate that study in the first half of next year. We are drafting the protocol and identifying sites for this study as well.

So as you can see, there is a lot of planning going on at Trevi as well as preparation work to align with the regulatory authorities and initiate multiple trials in the first half of next year. This takes time to ensure that we get these trials right. We will provide updates on next steps as we gain alignment and have line of sight to study starts.

I will now provide a quick review of the financial results for the quarter. The full financial results for the 3 months ended September 30, 2025, can be found in our press release issued ahead of this call and our 10-Q, which was filed with the SEC today after the market closed.

For the third quarter of 2025, we reported a net loss of $11.8 million compared to a net loss of $13.2 million for the same quarter in 2024. R&D expenses decreased to $10.1 million during the third quarter of '25 from $11.2 million in the same quarter last year. The reduction was primarily due to decreased clinical trial work in which those trials were actively enrolling in the prior year and reported data in the first half of this year. This was partially offset by increased costs related to our recently completed Phase I study and personnel and related expenses.

G&A expenses increased to $3.8 million during the quarter -- third quarter of 2025 compared to $2.9 million in the same quarter of last year primarily due to an increase in professional fees and personnel and related expenses. The increased professional fees were primarily due to increased costs as we continue to prepare for compliance with SOX 404(b) regulations.

As of September 30, 2025, our cash and investments totaled approximately $195 million. Our cash and investments gives us cash runway into 2028, subject to finalizing the development for each of our indications. We expect to be able to fund 2 Phase III trials of Haduvio for the treatment of chronic cough in patients with IPF along with a long-term extension for those trials, our planned Phase IIb/III trial in chronic cough in patients with non-IPF-ILD, our next trial in patients with RCC and our ongoing Phase I supportive studies.

So in closing, Trevi is positioned with strong data in 2 serious chronic cough conditions and is preparing to advance into the next stage of development for each of the 3 chronic cough indications. Chronic cough is a debilitating condition for which there are currently no FDA-approved therapies. Also, the company is financially strong with enough cash to complete the next stage of development work to potentially advance these therapies closer to the patient. We believe we are well positioned to execute our strategy and create meaningful shareholder value over the next couple of years.

This concludes my prepared remarks. Jim, Farrell and I are now happy to answer your questions. I will turn the call back over to the operator for Q&A.

The first question comes from Ryan Deschner with Raymond James.

Have you narrowed down more of what inclusion/exclusion criteria you would target for the non-IPF-ILD study, maybe in terms of, in particular, what constitutes chronic cough in those studies? And would you exclude any ILDs from an initial study in the space off of that?

Ryan, this is Jim. So the -- we had some good discussions with our KOLs for the non-IPF-ILD study. I think you can imagine that there's going to be a lot of similarity in the underlying lung disease. We'll define that in a certain way. Chronic cough, I think we're going to go in with the standard criteria. Typically, we look at some minimum amount of cough in terms of maybe 10 coughs per hour. So it will be very consistent with what we're looking at in the rest of our program.

So I think that those are narrowing down rather nicely. I think the important point to remember about that type of trial is that while there's going to be patients with lots of other comorbid conditions, we're really focusing on the entry criteria being related to the amount of cough that they have and the amount of lung damage, lung fibrosis that they have. So those are going to be the defining features for the inclusion. And then there'll be other things to manage around their comorbid conditions.

And Jim, anything we're carving out?

At this point in time, we're not really carving out anything. We're going to base it on those basic criteria. So of course, it's a broad swath of conditions. And as we get closer to that inclusion -- or it's closer to defining that protocol a little bit more in depth, we may carve out 1 or 2. But for the most part, it's going to be based on lung disease and amount of cough.

Excellent. And maybe quickly just on the DDI study. Would you anticipate needing to do any more studies like that for a trial like this or subsequent trials outside of IPF chronic cough and RCC?

Yes. So that's great, Ryan. So the study we got done was a DDI looking at our drug with pirfenidone and nintedanib as the key antifibrotics in this space. There will be other DDI studies that will be having to do based on the mechanism of drug metabolism. We are metabolized by CYP, primarily the 2C9 and 2C19 species. So there will be a DDI looking at probably a 2C9 inhibitor. These are things that we'll talk with the FDA about. But it is expected that we will have to do a couple of more Phase I studies and at least one more DDI study.

And the next question comes from Annabel Samimy with Stifel.

I just wanted to clarify. For the respiratory study, you had interim results from the DSMB saying that you didn't have any issues. Do you need to complete that study before you have the end of Phase II meeting with FDA? And is there any other hurdle that you need to get past for that specific meeting?

And then separately, if you could just share a little bit of the feedback that you've been hearing from the CHEST meeting at this point. How are the pulmonologists looking at this? And how do you start thinking about targeting the market that you're looking at?

So on TIDAL, we had a sentinel cohort of 4 subjects that we completed, and the plan was to have our data monitoring committee review those subjects. That all went fine. There was no safety issues identified, so we continued on. To answer your question, we will have the available data when we submit the package. We don't have to complete that study before we submit for the end of Phase II meeting. And our intention is that we'll have all the data by the time we have the meeting.

Yes. And I'll just jump in at the beginning of the second question. Then Farrell, I'll have you take on how it targets the market. But I think, Annabel, we presented -- we had our data presented at both CHEST and ERS. It was very well attended. We had one poster at ERS. You could barely even get near the poster. A lot of interest. What's interesting, there was a lot of our investigators that were very interested in the full data, and they've got their patients coming back to them wondering when we're going to start our next trial.

So I would say people understand cough is a big problem, and there's been a lot of work done in antifibrotics, but there really hasn't been a lot of work done on things that matter day-to-day to the patient. So we're getting a lot of attention in our sessions. The data has gotten a lot of attention. And we also hosted a reception one night that was very well attended by U.S. investigators interested in getting into our study. So really encouraging. Jim and I were both there and quite busy the whole time.

I think, Farrell, I'll let you take on sort of based on the feedback, how you might be thinking about targeting the market with any of the feedback.

When we look at the market, we do need to raise the burden of the disease, and that's work that's undergoing that we're continuing and we'll launch next year. There's also just targeting in terms of how we look at segmentating this market. It's work which we'll start next year just to make sure that we have appropriately sized our field force to target the key prescribers in this area. So that's some of the work. And then we're continuing to always do physician and payer research to understand how our new target product profile based on the positive results are seen by physicians and payers within this space.

And the next question comes from Leland Gershell with Oppenheimer.

Just a couple -- I joined a little bit late, so my apologies if you may have covered. But as you head into the end of Phase II meeting, are there any particular questions or issues that you would like to address your clarity on? And then I also wanted to ask on the drug-drug interaction side. Is there any need for Trevi to run interaction studies in patients who may be on other opioids concomitantly?

This is Jim. So in terms of the end of Phase II meeting, our standard questions are going to be related to the protocol design, endpoints, duration of the study, really nuts and bolts around the Phase III. We'll be submitting a full final draft protocol to them. So they'll have the protocol with them in hand. And we will guide some of the more important questions regarding the design, patient inclusion, exclusion criteria, our statistical approach, pretty basic things that are really important to narrow down at this meeting. So we will have absolute clarity on what we need to do for the Phase III coming out of that.

Safety database size, too, is an important one, right?

Safety database size. We'll be discussing the extent of any long-term data collection. And we'll also be -- as we've talked about the DDI study, and we did talk that we may need to do some more work in the Phase I world on wrapping up things for the NDA submission. We will probably do another drug-drug interaction study that encompasses our mechanism of drug metabolism, which is through CYP systems and 2C9 -- 2C19 in particular. So we'll be asked to do a drug-drug interaction study with drugs that are inhibitors of that system to understand what the effects are on pharmacokinetics. There might be some other Phase I studies that we're anticipating that we will discuss with the FDA at the end of Phase II meeting as well.

I would just add, though -- Leland, I think you specifically asked about other opioids. They are contraindicated. We have excluded them because, as you know, our mechanism is a new antagonist. So if you're on other opioids, it will put you into opioid withdrawal, which is obviously super helpful from the addiction side and labeling side. But we do contraindicate that in our trials and will be in our label.

And the next question comes from Judah Frommer with Morgan Stanley.

Maybe could you help us with latest thinking on potential to incorporate the non-IPF-ILDs into the Phase III program for IPF? Will you get any clarity on that at the end of Phase II, do you think? Or do you have to wait for that subsequent interaction? And then what are your thoughts on launching with both indications in the same label versus sNDA? And then secondarily, obviously, very high level, but any thoughts on changes in CDER leadership and impacts of the program?

I'm just going to comment on strategy. We could probably both do this. But I think, Judah, we made a decision that we're going to go in with sort of our strongest foot forward and do the end of Phase II meeting. Jim's got a lot of data, robust data. We want the FDA to catch up with where we are, all the studies we've run, the data we've generated. And we will tease up there that our broader program includes both RCC, but importantly, non-IPF-ILD, which we think shares a common biology.

So we will tee that up. But you only get 1 hour in this meeting and we don't want to get distracted debating non-IPF-ILD there, because to Jim's point, we need to walk out with clear guidance on our Phase III program. So really trying to protect that and keep it whole.

As soon as we feel we have alignment with the agency, we're going to be prepared to submit a protocol in non-IPF-ILD and request a Type C meeting. Hopefully, that's a pretty easy act coming off the heels of the IPF end of Phase II. So that was sort of a strategy point because we could have jumped in earlier, but felt we wanted our strongest foot forward.

I mean as far as the sort of CDER change in leadership -- and I'll let Jim add any color as well. I mean, obviously, a new person named this week, oncology person. I don't know how much that's really affecting the division. We've had -- I mean, baffling to me -- timely feedback on time, clear communications. I don't know how the FDA is holding it together. Kudos to them.

So I don't know how much those levels are affecting things when you're in a clinical trial mode. I'm sure at the point in time they look at your NDA, it does. But it hasn't seemed to impact what we're doing. I don't know. Jim, do you have anything to add?

No, nothing to add to that other than I think the surprise factor of how responsive they've been has been high on my list. It's like this is very unusual for me to get this kind of responsiveness. So I'm very pleased about that.

Yes.

And the next question comes from Serge Belanger with Needham & Company.

I think in the past, you've discussed the potential of Haduvio being eligible for orphan drug exclusivity in IPF cough. Just curious if you have any updated thoughts on that? And whether that's something you will seek like an orphan drug designation in the upcoming end of Phase II meeting with FDA?

Jim is laughing because he made me promise -- we are going to request orphan drug for IPF. I do always warn people that -- I don't want people to put too much in that, although IPF has gotten orphan drug. This is cough, and IPF in cough is a broad problem. So we'll see what they have to say. So we will apply. I think it's an answer we should know. Jim made me promise that we wouldn't do that until after we went through our end of Phase II meeting. He doesn't want them distracted on any other side questions. So I think on the heels of end of Phase II, we'll go ahead and submit for that and find out their views on cough and IPF.

And the next question comes from Roanna Ruiz with Leerink Partners.

So a couple for me. First one is, given the evolving IPF landscape with recent positive data from United Therapeutics' TETON study, I was curious how could that impact how Haduvio fits into the prescribing approach and treatment algorithm of physicians?

Farrell, do you want to take that? Or I can as well.

Yes, happy to. If anything, it probably -- it doesn't really change much for us. When you think about chronic cough, the high burden of disease among these patients, physicians look at this as either first or second-line therapy. And that could be before an antifibrotic or after an antifibrotic is initiated. When you look at the drugs and the new approvals that are already coming to market, they're still slowing the progression of the disease and they're not having a positive impact on the cough. So there's still a very high place for chronic cough therapy and concomitant therapy with these antifibrotics that are on the market or potentially coming to market.

And Farrell, I would just add, too, I've heard a lot of discussion about -- with improvements in therapies and treatments for patients, it probably just improves the diagnosis. The patient groups will start to grow. Then people are focused on this disease a little more. Hopefully, cough comes to the forefront when we actually have something for treatment. So it's obviously great for the patient to have options. But I just think overall, it probably grows the market as well.

Yes, makes sense. And a quick follow-up about the TIDAL study. What do you hope to see in the results in terms of a best case scenario now that you can complete enrollment? And any sort of thoughts on how that might impact the end of Phase II discussion with the FDA?

Yes. This is Jim. So we are looking at basic respiratory function, PO2, CO2 and respiration rate. So the FDA was interested in a study like this just to make sure that we don't have any latent signals regarding respiratory depression. So we're taking a very fundamental approach on key respiratory parameters and looking at those. The ideal outcome for the study -- and the data have been great so far -- is that there's no findings here. There would be no findings, meaning that there's no changes on any of those parameters.

We are dosing at night, looking at these IPF subjects while they are asleep, which is considered a conservative way, most sensitive approach to this. So that's the nature of the study to really pull out if there's anything there. So obviously, clean results and no impact on the program is the ideal outcome here.

Jim, I would just add. We've obviously had this in, what, 200 people now, IPF patients clinically and never seen any signal. So I think this will just sort of go hand-in-hand with the safety database that they look at as well.

Absolutely.

And the next question comes from William Wood with B. Riley Securities.

So a couple from us kind of focused on the Phase III. It sounds like from what I can tell, you've essentially got your sort of Phase III package sort of put together in terms of how you want it. Obviously, that's got to be discussed with the FDA and approved or at least agreed upon. But I was just curious if you could walk through sort of maybe what you're thinking at a high level in terms of doses and/or timing, titration you're looking to take forward?

And maybe just remind us, are you going to allow patients to use background antifibrotics in the study? And will you be looking at biomarker -- fibrotic biomarker improvement within the study? And then lastly, just briefly, will this be conducted in the same sites that your other Phase IIs were? Or will you be branching out further?

Sure. I think I can remember all those...

I got them written.

I got them, got them. So William, this is Jim. So in terms of doses, we did –- CORAL was a great study for us because we learned a lot from it, including -- that was our definitive dose-ranging study. So in terms of doses going forward, we did a lot of work over the summer. We interrogated the 54 and the 108-milligram dose group. And because of the titration up, we were able to determine in individual subjects and looking at dosing groups that the 108 really didn't add any significant value to the 54-milligram BID dose. So 54-milligram BID will be our top dose going forward.

The 27-milligram BID dose is a titration dose. We identified that as a minimum effective dose in the CORAL study. So it will not be considered a treatment dose, but it will be considered a titration dose. What we also learned from the CORAL study is that when we do our titration, as we've done in all of our programs to date, we see that most of the adverse events that we see typical for this compound, which are mostly GI and CNS in nature, most of those come on with the initiation of dosing. So what we're going to do is extend a little bit further the once-a-night dosing under the 27-milligram dose, go into 27 milligrams BID and then get into our 54-milligram BID treatment dose.

So we will extend that titration period a little bit to mitigate some of the earlier side effects that we see with the compound. And just a reminder about the nature of the adverse events that we see with nalbuphine is that we typically see some GI and some CNS. These are typically transient and these are typically things that do tolerate out over time, and that's why we're going to extend that titration period.

In regards to your question about allowing background antifibrotics, over 80% of our subjects in the CORAL study were on either nintedanib or pirfenidone. So yes, we are going to allow approved antifibrotics as background medication. In terms of biomarkers, we don't have any intention of looking at those in any -- well, we're not going to look at those.

And in terms of the sites, if you recall, in CORAL, we were running those study -- that study ex U.S. We will be going back to the more successful sites in that region. And we will also be bringing in a large number of U.S. centers. The great thing about the Pulmonary Fibrosis Foundation is that there are over 80 excellent care centers, and we are talking to them about conducting our trial. So we will be bringing in, in a major way U.S. centers as well as Canada and Europe.

Got it. That was very helpful. Very briefly and lastly, the end of Phase II package, once you actually get that submitted and discussed, will you be relaying that to us and/or investors, the public? Or is that just -- how will that be dispersed, I guess?

Yes. No, it's a good question, William. I think typically, you do the meeting and then you wait 30 days for the minutes. Usually, you want to wait to see the minutes so that what we think we heard we actually see in writing when we get it. When we have that information, we'll definitely give an update to the Street. I mean we probably won't put out a separate press release. I think on one of our earnings calls or some venue, we'll use it to update people. But yes, it's important information for sure.

The next question comes from Kaveri Pohlman with Clear Street.

So my first question is about how well do the current trial match the real-world patients considering things like the inclusion/exclusion criteria, comorbidities or use of other drugs? And for future trials for both IPF and RCC, do you plan to make the eligibility criteria broader to include a more diverse population? Or will they stay the same?

Yes. This is Jim. So we will keep this population for the Phase III as broad as possible. We are really trying not to make it strictly a clinical trial population, but we want to keep it broad. So we are working with the KOLs to really refine our inclusion/exclusion criteria to make it definitely more real world. So we will have a few restrictions other than -- they need to be diagnosed with IPF. They need to be -- have some other things that make them relatively healthy that they can actually be involved in the study. So I can promise you that it will be as broad as possible, as real life as possible.

Not too much different than our IIb, right?

Not very much different. In fact, we're actually refining a few things to broaden it from our IIb. We will allow basically -- unless something that is going to interfere with our ability to measure cough or will have a direct impact on cough in the trial, their con-meds will be allowed to -- per normal. And I don't know if there's anything -- what else -- was there anything else that you asked? I think I covered those 2 things. Okay.

Right. Yes, that's helpful. And I also want to understand for the RCC Phase IIb trial, do you plan to study the same dosing regimen as it was in the Phase IIa? Or you plan to kind of test QD options also since the drug seems pretty safe?

Yes. We're actually going to probably eliminate the top 108 dose in that trial, and we will be exploring QD dosing, once-a-day dosing, in that trial as well.

As well as BID.

As well as the BID. So we'll probably add a 27 QD arm in there. Because if you recall the data, our 27 BID dose was about as effective as the 2 higher doses.

Got it. And maybe just like a last one. So respiratory safety study, it was surprising that the FDA needed that after you showed 200 patients worth of data. But I still want to understand, will you be assessing long-term effects? Do you need to keep patients on to provide that data? Or it's not required?

So I think the FDA is curious about doing a very specific study. I've been in the situation before where they like to see a more directed controlled study rather than collecting adverse events. So I think it's, if they're probably asking for a study like this, I think it's going well. I'm sorry, what was the second part of your...

Long term. I mean [indiscernible] long term.

We will do long-term data collection in our Phase III program. The anticipation based on previous FDA experience here is they'll be looking for something like 52 weeks of safety data.

I'm not showing any further questions. This concludes our question-and-answer session. I would like to turn the conference back over to Jennifer Good for closing remarks.

Thank you. We appreciate you joining us for today's call. I know this is the end of earnings season, so you're all probably happy as well. Enjoy the upcoming holidays. And we are available after the call or tomorrow for any follow-up questions that you may have. Thank you.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

Welcome to this session of the Morgan Stanley Global Healthcare Conference. I'm excited to welcome the team from Trevi.

Before I do that, let me read a quick disclosure statement. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

So with that, Jennifer, Farrell, thank you for being here.

Maybe we could just start with an overview of the company for those who might be less familiar, or newer to the story? That would be great.

Yes, happy to do that. And thank you to everyone that came. I see some old friends in the audience. And Judah, thank you to you and Morgan Stanley, our newest relationship, newest analyst. That's great.

So Trevi has had a strong year. We are a single-asset company. We have a drug that's broadly in the opioid category but is in a subcategory of mixed agonist-antagonist. We'll probably talk more about that. What's interesting about it is you get the benefits of opioids, good efficacy, good safety without the addiction potential. So the drug has been around. It's been unscheduled. So we can get more into that later.

But what's unique about that mechanism is it works both centrally and peripherally. So I'm one of the two cofounders of the company. I co-founded it with the neurologist. Tom, my co-founder, was interested in looking at places opioid biology played an important role outside of pain. And so one of those areas we explored was cough, chronic cough. And Tom was thinking a lot about it as conditions that cause sort of a wind-up neurological phenomenon, which is why the central mechanism is important. That has sort of landed our way towards three legs of the stool that we're building out here, very capital efficient.

It's one drug, three indications, all in cough. The first is in chronic cough and idiopathic pulmonary fibrosis. We can get more into the market of that. But you probably know IPF is a tough diagnosis. People typically die in about 3 to 5 years, and 85% of them have chronic cough. So it's a big part of that disease that they struggle with.

The second leg of that stool is other interstitial lung diseases outside of IPF, and essentially what they all share in common is fibrosis and cough. So with our strong IPF data we decided that we're also going to bolt on sort of the other half of this equation of non-IPF/ILDs.

And then earlier in March, we had also looked at a space called refractory chronic cough, which some of you may know. There's been a lot of companies. I think there's been like 20 assets studied there. All have failed except for the BELLUS/GSK drug, which GSK ended up acquiring BELLUS for that program a couple of years ago for about $2 billion. They are now in late-stage Phase III programs. We think that they -- while they may be first to market, our data was much stronger. So we think we have the ability to be best-in-class.

Farrell will talk more about this when we get into it. But commercially, the way we're going to tie all this together is leading with our specialty strategy in pulmonology, high pricing targeted commercial footprint. And in RCC, the way that pulls in because that's a very big patient population as we will go after treatment-resistant patients and maintain that pricing.

So again, super focused model. We are heading into Phase III in our IPF program. So our next key milestone is an end of Phase II meeting. We'll look to launch ILD in parallel, and then we've got to do some dose finding work around refractory chronic coughs. So yes, it was a productive year for us. I think we have a strong focus, and I just need to align with the agency and keep moving.

Okay. Great. So maybe we start going a little bit deeper on the competitive landscape. Like you said, there're some drugs in Phase III studies as one approved drug outside the U.S. in refractory chronic cough. How well these drugs work would you say in general? What are patients doing to manage symptoms here?

Farrell?

Yes. So when we look at the competitive landscape in IPF and ILD, really, there's no approved therapies. One thing that we know about the drugs that they're using is even the antifibrotics, they don't benefit the cough. They don't worsen it, but they definitely don't provide a benefit to it. So it's really a wide-open landscape.

There's really only one other asset being studied there by BI. That is a peripheral-only mechanism. So getting back to Jennifer's point, the differentiation we have is we work broadly. We work a rapid effect in a large proportion of patients. That mechanism that they're studying has also unfortunately failed in refractory chronic cough with two other companies.

When we look at refractory chronic cough, as you mentioned, Judah, gefapixant is approved ex U.S. They had challenges in the U.S. They will not commercialize here in the U.S. And the challenges they really have is this is once again a peripheral mechanism. And it -- it's part of what they try. They try Tessalon Perles, they try all these other therapies, but they really don't work, and they don't last.

Okay. That makes sense. Just thinking about kind of historical chronic cough trials, you've seen significant placebo responses. It does seem to vary based on indication and trial design. But can you talk about placebo responses in chronic cough generally and how you're managing that for Haduvio's development?

Yes. So I'm going to break these into two buckets because in IPF chronic cough, the placebo effect has been pretty well behaved. It's been sort of 15% to 25%. We just saw in our 165 person trial that we had just under 17% placebo response, which is pretty standard, I think.

We believe that's because you've actually got fibrosis in the lungs that's triggering this cough. So trying to overcome that with placebo very difficult. Refractory chronic cough has been a big problem. I mean, Merck, which was sort of the first guy over the wall here, had to figure all this out. They saw a 50% placebo response, which is just way too high. And I think there's been a lot learned in refractory chronic cough.

I think when Merck ran the study, there was less rigour around making sure all the other sort of comorbidities has been excluded. If asthma has been treated, or GERD has been treated. I think now BELLUS did a nice job of sort of making sure they adjudicated that. They've got the right patients. I think the other big part of this is keeping a tight study. If Jim was here, our development colleague, he would say it's all about getting the right sites, the right patients.

I think because these peripheral-only agents have a small effect, they need a lot of patients in their study. I mean -- and GSK is almost up to 1,000 patients. Now we will need nowhere near that. When you do that and you're running two studies. You have to go to a lot of sites, and that's when you sort of lose control of this. So it's not been a problem in IPF. RCC, it's definitely something that's got to be tightened up and paid attention to.

Okay. That makes sense. And you're starting a Phase III IPF program next year. I know you're still in the planning stages, but what can we think of in terms of trial design, maybe relative to the Phase II program?

Yes. So our Phase IIb study is a good comp actually. It was a dose-ranging study. It was 6 weeks long. The primary endpoint was an objective cough monitor. We had several secondaries. When you fast forward to what our pivotal program looks like, it's a little bit of rinse and repeat. It's the same primary endpoint. It will go to 12 weeks instead of 6 weeks. That's what we're proposing to the agency.

Same second -- the secondary endpoint we used in that cough severity numerical rating scale will be our key secondary. So a lot of the same things. We also get the ability to tighten it up a bit. We've selected our dose. So not a lot of new learnings here though. I feel like CORAL was a really good study to derisk where we're heading with that.

And can you give us an idea of size of the study relative to CORAL? Again, you mentioned that effect size, which should control...

Yes. No, that's worthy of a discussion because if we only had to power the study based on objective cough count, we would only need about 30 to 40 per arm. So we're only taking one dose forward and placebo. Obviously, we'd never get enough numbers for the safety database. But we also have to hit on our key secondary, which is the cough severity NRS.

And we think this is all going to be in play in the end of Phase II meeting. But we think we need to have a responder analysis around that. So that drives the numbers up a bit. When you think about getting enough patients for your safety database, we're planning on about 250 patients per arm -- per study, I'm sorry.

Okay. That's helpful. And then you'll also be initiating a Phase II study. In a new group of patients, like you mentioned, the non-IPF/ILD indication. So what's the incremental opportunity in these ILDs maybe from a patient number perspective? And how similar is the cough to IPF?

Yes. So Farrell, go ahead.

So when you look at IPF, just to ground us in the IPF opportunity, there's about 150,000 patients in the U.S., about 2/3 of them have uncontrolled chronic cough. When you look at non-IPF/ILD, it more than doubles that. So you have about 225,000 patients, and that excludes sarcoidosis because those don't always present as fibrotic lung disease. And about, call it, 50% to 60% have uncontrolled chronic cough.

So really, the underpinning of this is that they have a level of fibrosis, and they have chronic cough. When we asked an ad board, we had one at ATS earlier this year with ILD experts. And the first question we asked them is, do these patients cough and does it present differently? And all of them overwhelmingly said, no, these patients have a huge unmet need. There's still nothing being studied. So they present similarly.

Okay. Is there anything from a mechanistic perspective that might make you think that Haduvio wouldn't work in these patients versus working in IPF?

I mean they were pretty adamant. You've already studied these patients. IPF is an ILD, it's fibrosis and cough. I think the biggest risk with this study is making sure they're stable on what other comorbidities they have. There's a broad range of things here that patients can look like. I also think variability will be a little bit of an unknown, maybe more variable. We're going to power around our IPF study.

But we had a good discussion around that, that we think that's a risk we're taking. We'll probably build into it for anybody who's followed us for a while. We like to use the sample size re-estimation, which we won't do in IPF. We don't need it anymore. But think in this ILD study midway through, we'll sort of recheck the powering assumptions, make sure there's not something about variability and go from there. So that's probably the biggest risk.

Okay. And maybe can you take a couple of minutes and walk us through clinical development pathways for the non-IPF/ILDs. I think you've talked about potentially marrying it with the IPF study. So maybe if you could just remind us of the interactions with the agency and how that will inform how these programs both move forward?

Yes. So our interactions with the agency to date have all been around our IPF program and pretty early pre-IND kind of discussions and then things along the way as we've been finishing different studies. But the end of Phase II is a really critical meeting. And we had a lot of discussions this summer. We were talking about Dr. Makary and he's saying all the right things, how we want to sort of lean in on that, where is the right place to lean in.

What we've decided is we're going to go in and propose two IPF studies, even though I do think there's an argument to do one IPF study, I think because that's rinse and repeat, huge indication, first one across the finish line, we don't want to mess with that. And sometimes FDA, there's no set guidance on when you get away with one study and when you don't. So you always take risk there.

I think where we're going to lean in to your question, Judah, is on the non-IPF/ILD. We're going to run that in parallel. That should finish enrolling pretty quickly because it's the same centers you're in. A patient comes in, they either have IPF or ILD in these ILD care centers. So we think we can enroll that quickly, and we're going to talk to the FDA that if that's positive, could we merge that in on the indication statement for cough and interstitial lung disease.

If that answer is no for any reason, then ILD just becomes an sNDA and it follows by 10 months. So there's sort of no downside. We're just trying to close that gap if it's possible. I think we're not making the strategy up. Antifibrotics, they typically do one IPF, one ILD. We just didn't want to put our IPF program in any kind of risk, so that's how we're thinking about it.

And just remind me, the sequencing of the two meetings with FDA, the end of Phase II versus what the other type would be, but just the sequencing of those.

Yes. So we, again, all debated sort of what you lead with. We decided to lead with IPF because it's our strongest data set. We have a lot of data. The data is super compelling. We also know the things the FDA was focused on from a safety perspective. They wanted to see drug-drug interaction study with the other antifibrotics. We're finishing that now. They wanted to see our human abuse potential study, which is done.

And they've also wanted to see our respiratory physiology study, which we're in the process of and we'll have. On the heels of hopefully, a constructive end of Phase II meeting, we're going to let them know there that we plan to come right back to them to discuss the ILD piece of this and we'll submit the full protocol and ask for a Type C meeting. So we're going to lead with IPF and follow right on the heels of ILD. Refractory chronic cough, we actually don't need to talk to them. We can just sort of keep moving on that program.

Okay. That makes sense. And just speaking of mechanism here, right? I think we've gotten the question on concerns about abuse potential. You're doing the abuse potential study. But what have you seen so far in your studies that could point toward abuse potential or posing of a commercial risk? Or is that less relevant than maybe investors think it might be?

Yes. I always joke to investors, doctors, patients and strategics don't really dig into this. It's investors that worry about it. And I get it. The O-word is a bad word in today's society. I think to answer your question directly; this drug is a known entity. It's been around for decades. It's been unscheduled by the DEA. The reason it's unscheduled is when you think about fentanyl or morphine, those are all new agonists.

That's where the addiction comes in. This -- there were four drugs developed to actually get away from addiction. So nalbuphine is a mu antagonist like Suboxone and a kappa agonist for any of you that followed Cara. Neither of those mechanisms have ever been scheduled. So there's good precedence, nalbuphine hasn't been scheduled. We ran our human abuse potential data. We believe it's very supportive of that same profile.

I think the last key piece of the puzzle is we'll have to submit what they call AEs of Special Interest from our full clinical development program. That's things like euphoria, hallucinations, et cetera. We've seen very little of that. I mean we've published all of our AEs. It never makes any kind of chart of numbers. I mean, yes, there's one-off things, of course, like we all would have. But yes, nothing there we're really particularly worried about. So feel good about that situation.

Okay. And how are you thinking about, I guess, in terms of scheduling, if you end up in a place where maybe sleep aids are, how do you think that impacts commercial potential or...

Yes, Farrell did a lot of work on that.

Yes. So when we did work in the IPF/ILD space, I mean, this is a terminal disease with a high unmet need. It really doesn't have much impact when we've done our research with prescribers, and we have a patient ad board as well. They care about efficacy and safety first, and we definitely tick both of those boxes. Even if we end up in a Schedule IV, there's minimal restrictions on that. We can still sample.

We can do all the activities we need for trial and awareness. When you look at the RCC, I think people normally have a bigger question of does this have a larger impact in that broader population. Especially with our strategy of going to treatment-resistant RCC, we think we minimize that impact because most of them would flow through specialist centers. Maybe you have about a 20% impact, but it's still going to be minimal in that. I mean our base case is this remains unscheduled.

And Farrell, maybe mention the claims database work you did, too.

Yes. When -- there's a nice paper that was published a couple of years ago in the U.S. in the Midwest of the claims database and it shows that in chronic cough broadly, about 71% of prescriptions are opioid-containing cough suppressants today. So these are therapies that are actually probably posing a potential harm to these patients because they do have a level of addiction, codeine, a level of morphine, hydromorphone, there's neuromodulators. They fall in that category today. So we actually have a public health benefit that we could potentially provide by providing this therapy with a lower relative abuse potential.

Okay. Got it. And just thinking, I guess, a bit further about commercial strategy here. You mentioned it's possible IPF and ILD go at similar times. I guess how could that potentially pave the way for RCC? How much overlap is there like you were talking about in terms of centers?

Yes. So IPF/ILD, the nice part is there are ILD centers, so that encapsulates IPF just naturally. There's about 80 of them in the U.S. Pulmonologists would be a primary call point for us, and we'd stay there for that indication. We think we need probably about 50 to 75 reps in order to cover that universe. We've done some work. I think a really nice analog is Verona within that space, right?

Verona is covering a much larger call target, about 14,000 physicians with about 125 reps. So we think we're in the right range there, but we'll do some more work. The question, as you say, is then what does RCC mean? As a small single-asset company, we look to stay focused. Pulmonology will be our primary call point.

We may look to add one other specialty that's incremental, maybe something like allergists, small, focused specialty that we'd be able to handle ourselves, not incrementally really change the sales footprint. But in that sense, we'd be able to stay at home. Now a multinational may handle that a little bit differently, but we think that we can cover most of the market. About 1/3 of the market is covered there and probably the treatment-resistant patients are there as well.

Okay. Got it. And is pricing a consideration if you add on the RCC indication?

It's less of a consideration in terms of price. So we think we will lead with specialty pricing in IPF and ILD that really is irrespective of if we come to market with IPF first or the combined indication. We've looked at $60,000 to $85,000 in range, and we just continue to see pricing as inelastic. I think the Insmed launch in bronchiectasis with a much larger population at $88,000 is a great benchmark for us, really paves the way. The question on transition to RCC, it's less of pricing because we'd look to take that same specialty price into that space.

But in the treatment-resistant space is what other restrictions could we get from payers, quantity limits, we'll take those reauthorizations in order to maintain the specialty price point. There's also one avenue we're looking at RCC where we may interrogate lower dosing, which may be lower QD dosing that gives us a little bit of flexibility in terms of pricing differential, second brand potential. We'll have to see what comes out of that study, but we think it could provide some upside.

Okay. Interesting. Another question we get is just on IP for Haduvio. Does method of use cover both IPF and RCC? How are you thinking about kind of the broad patent family?

Yes. So just broadly, old drugs, so no composition of matter. So we've been from the early days working on method of treatment patent coverage. We have a broad description out there that covers all these various forms of cough. And when we get data, we pulled out the IPF claims, we prosecuted those, actually got all the claims filed with no changes to them. Unfortunately, the whole game in sort of method of treatment is there wasn't -- there weren't -- there isn't prior arch that you're trying to step through.

And we all know 10 years ago, there wasn't work going on here, particularly in this class of drugs of mixed agonist-antagonist. So the IPF patent has been issued. We've just pulled out the Track One claims around non-IPF/ILD to get those issued. And RCC is down to the very final sort of question from the examiner, which isn't surprising, which is refractory chronic cough a generic term or a defined term, fair question.

So we've got the sort of world-leading expert on that, that's going to get on and explain to him, this is indeed a diagnosis and that should get issued. So those go through 2039. We also are spending time working with our patent counsel clearly about other kind of dose claims that come out of all of our clinical work. And those will just continue to add on to that IP.

Okay. Great. And maybe before we close out the company-specific portion of the questions, can you remind us of cash runway and which catalysts we've discussed that will fund?

Yes. So we raised money in June off of our CORAL data. We have just over $200 million at the end of June. This model is actually quite capital efficient because it's sort of one drug that you're developing, three indications, all in cough. And as Farrell explained, a lot of overlap in IPF/ILD, same centers, sort of very good learning. So anyway, with that money, we can do our two IPF trials, the long-term extension, the non-IPF/ILD study and the refractory chronic cough IIb.

We think all that should report out by the second half of '27. And we have cash that runs into late '28, early '29. So we've got some good room to move. So we're coming up with other ideas of how to spend that. There's actually some interesting stuff coming out of the data as we've really dug into it that we may try to dig into and pull out even more.

Okay. Great. I should mention before I get into kind of the mini survey that we're asking all of our management teams. If there are any questions in the room, feel free to raise your hand. We've got microphones that can circulate. All right. So maybe just kind of this mini survey that I mentioned.

So biotech does seem to be more exposed to external and macro factors of late. So we're asking each management team the following three thematic questions. First is China's rise in biotech innovation. How are you thinking about your competitive position here? Will this influence R&D or potentially business development strategy, if it's less relevant, that's fine, too.

Yes. No, that's fine. I mean we're a single asset, small 35-person U.S.-based drug development company. Having said that, obviously, we keep our eye on the broader ball. I would say we're not -- our strategy is not to in-license other things. We can create so much value with these indications, and Farrell sort of do the whole walk-down math, but each of these indications can be $1 billion to $2 billion each.

So we're talking about a big drug. So we don't need to go look for other things and get distracted. I would also say, and Judah, you may know this even better than I do. But as I understand in China, there's sort of some therapeutic areas like oncology that are a big focus for them. Respiratory to date hasn't been a problem. So I don't really worry about them to date from a competitive perspective. So really not impacting what we're doing.

Okay. Makes sense. The second theme is AI. Would you say Trevi is leveraging AI or thinking about AI potential to disrupt the space in any way?

Yes. So I'll let Farrell answer this because he's much more informed on it than I am. I've made this edict I'm never learning AI. I'm too old.

I mean we actually had a steering committee, IT steering committee meeting yesterday exactly on this topic. I mean we look at AI in two ways. One, how do we make our work more efficient, how do we drive better decision-making. I think it really revolves around that. As we get closer to commercialization, AI will definitely play a part in that in terms of the targeting strategy and commercial strategy itself, it will play an integral role.

Our regulatory team uses it a lot, too, to search regs and what's new and what's coming out. So yes, a lot of use there.

Okay. That makes sense. And last is hopefully most relevant. Just on the regulatory side of things, changes at FDA, MFN pricing, tariffs, anything on the regulatory side of things that is driving internal conversations of the company.

Yes. I mean we watch it all. The obvious one that's going to be hugely impactful for us is FDA. And I think in our mind, there's a question of what the gap is between what Makary says and what's happening in the divisions. Our division, we're in respiratory pulmonology. It's been decimated. Fired the division head, a 1/3 of it's been wiped out. So now having said that, they've met all their deadlines with us.

They've come back with clear guidance. So I can't sort of say that we've seen any impact, but our end of Phase II meeting, I think, will be really telling. MFN, we're watching it. I think the reality is it's a small company, if MFN comes into play, we just won't launch in Europe. We'll be a U.S. company. And tariffs, we have no impact. We did a lot of searching around, but we do all our manufacturing here, all of our supply chains are here. So no impact from a tariff perspective.

Awesome. If there are no questions, I think we will leave it there. Thanks again.

Thank you, Judah.

Thank you.

Good afternoon, and welcome to the Trevi Therapeutics Second Quarter 2025 Earnings Conference Call. [Operator Instructions] Please note this event is being recorded.

Various remarks that management makes during this conference call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent quarterly report on Form 10-Q, which the company filed with the SEC this afternoon.

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so, even if its views change.

I would now like to turn the conference over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for our second quarter 2025 earnings call and business update.

Joining me today on this call are my colleagues, Lisa Delfini, Trevi's Chief Financial Officer; Dr. James Cassella, our Chief Development Officer; and Farrell Simon, our Chief Commercial Officer. Lisa and I will make some comments on the business and financial results, then the team is happy to answer any questions that you may have.

The first half of this year has been a major inflection point for Trevi, with positive data readouts in both the CORAL trial for chronic cough in patients with idiopathic pulmonary fibrosis, or IPF, and the RIVER trial for patients with refractory chronic cough or RCC.

As a result of this strong data, we were able to raise approximately $115 million in capital for total cash and investments at the end of June of approximately $204 million. This gives us strong runway to execute against several important clinical milestones in each of our programs. It is an exciting place to be in our journey, and we believe we are well positioned to execute our strategy and create value.

Let me provide a brief update on what we have been up to this summer. As you all know, the top line results from our CORAL trial were announced in early June with Haduvio meeting the primary endpoint with a statistically significant reduction in 24-hour cough frequency across all dose groups studied.

Since reporting our top line data, we have received the full data set from the trial and can confirm that the data across the secondary endpoints were consistent with the top line results. Importantly, the quality of life assessment in our patients using the Leicester Cough Questionnaire, or LCQ, showed marked improvement with a statistically significant reduction at both the 54 and 108-milligram BID doses.

The LCQ is a 21-point scale with 3 different domains: physical, social and psychological, an increase in total score of 1.3 points is considered clinically meaningful. For the 54-milligram and 108 milligram BID doses, there was a statistically significant 3.7 and 3.4 point increase, respectively, p equal 0.01 for the total LCQ score at week 6. These are strong results for a 6-week study.

The LCQ is meaningful in patients with IPF. In fact, the publication from the large U.S. Pulmonary Fibrosis Foundation Registry demonstrated that a worse quality of life as measured by the LCQ correlated with the risk of worse health outcomes such as respiratory hospitalizations and mortality.

One of our key focuses at Trevi is remaining patient-centric as we plan for development and commercialization. In a recent patient advisory Board meeting, we reviewed the CORAL results to get patients' reactions. The 2 most important factors to patients when looking for a future cough treatment, we're seeing improvements in cough frequency and severity and quality of life, similar to what we've heard from physicians.

Several patients remarked that with the kind of change in cough seen in CORAL, it would be incredibly impactful and positive in their day-to-day lives. I was struck by how much cough controls patients' daily activities and how they isolate or compensate to avoid the embarrassment of coughing out in public.

Coming off this data, Jim and his team have been very busy preparing for the end of Phase II FDA meeting and the next set of trials. We will provide more detailed guidance when we initiate each trial. But let me give you a brief update on the priorities over the next few months.

First, we are currently conducting a couple of important Phase I studies. We are working on completing our TIDAL study, which is studying the respiratory function and safety of Haduvio on IPF patients as well as conducting a drug-drug interaction study looking at any potential PK effects of nalbuphine when co-administered with pirfenidone and nintedanib, both antifibrotics that are taken by patients with IPF, and other progressive fibrotic diseases.

We expect to have the data from both of these trials in time for our end of Phase II meeting with the FDA. As for the end of Phase II meeting, we expect to request that meeting in the fourth quarter of this year. The key points we are looking to discuss with the FDA are to gain alignment on the Phase III program for cough and IPF, as well as any other NDA-enabling work, which needs to be completed.

In parallel, the team has been preparing to initiate the Phase III program in the first half of next year. We have also been preparing for a study in other non-IPF interstitial lung diseases. This population will include non-IPF patients that have lung fibrosis and cough. We estimate there are approximately 228,000 of these patients with 50% to 60% having uncontrolled cough. This more than doubles the market opportunity of IPF cough, and these patients are primarily seen by the same pulmonologists that see the IPF patients. This keeps our clinical and commercial efforts efficient and create synergies.

We plan to request a meeting with the FDA this year to discuss our study design for non-IPF-ILD and the protocol for this indication. Once we have FDA input, we will be prepared to initiate this study.

Finally, we have been working on the next study in refractory chronic cough. We expect that to be a Phase IIb parallel arm study design, looking at dose ranging and are planning to initiate that study in the first half of next year as well.

So, as you can see, there is a lot of clinical development planning going on at Trevi as well as preparation work to align with the regulatory authorities. This takes time to ensure that we get these next set of trials right. We will provide updates on next steps as we gain alignment and have line of sight to study starts.

I will now turn it over to Lisa to review our financial results, then we will open it up for any questions you may have.

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the 3 months ended June 30, 2025, can be found in our press release issued ahead of this call and our 10-Q, which was filed with the SEC today after the market closed.

For the second quarter of 2025, we reported a net loss of $12.3 million compared to a net loss of $12.4 million for the same quarter in 2024. R&D expenses decreased to $9.4 million during the second quarter of 2025 compared to $10 million in the same quarter in 2024. The reduction was primarily due to decreased costs related to our Phase IIa RIVER trial, our Human Abuse Potential study and our Phase IIb CORAL trial, all of which were actively enrolling in the prior year. This was partially offset by increased costs related to our recently initiated Phase I drug-drug interaction study and personnel and related expenses.

G&A expenses increased to $4.3 million during the second quarter of 2025 compared to $3.3 million in the same quarter of 2024, primarily due to an increase in professional fees and personnel and related expenses.

The personnel and related expenses were primarily due to increased headcount. Approximately $500,000 of the $1 million increase in total general and administrative expenses, was due to costs to prepare for SOX Section 404(b) related to our internal controls. These requirements become more rigorous as the company's market cap grows. As we continue our readiness efforts, we expect approximately this level of expense for the second half of 2025 and the expense may increase going forward.

As of June 30, 2025, our cash and investments totaled approximately $204 million. As Jennifer mentioned, the increase in our cash and investments was primarily a result of the successful public offering we completed in June 2025 after the release of the data from our Phase IIb CORAL trial that resulted in gross proceeds of approximately $115 million, including the full exercise of the greenshoe.

Our cash and investment balance gives us cash runway into 2029 and enables us to fund 2 Phase III trials of Haduvio for the treatment of chronic cough in patients with IPF, our planned trial for chronic cough in patients with non-IPF-ILD, our next trial in patients with RCC, the Phase I work Jennifer discussed, and it enables pre-commercial planning activities. In summary, Trevi is in a strong position financially to execute our business plan. This concludes our prepared remarks.

I will now turn the call back over to the operator for Q&A.

[Operator Instructions] The first question comes from Faisal Khurshid from Leerink Partners.

It kind of feels like a calm after the storm moment here. I wanted to ask on the respiratory depression study. Could you comment a little bit on the progress of this study and just what it entails in the logistics? And what I'm trying to get at is like for investors, should we think about this as just sort of like any risk involved in that study? Or how to kind of like think about the outcomes there?

Faisal, Jim here. Thanks for the question. So, our respiratory safety study, as you know, is about looking at the effects -- potential effects of nalbuphine of Haduvio on respiration, looking at rate, CO2 and O2 in patients with IPF. So, it is an assessment study. It's to characterize, if there's any effects there in this patient population.

I would say that, it's an informative study. It's a study that the FDA has been looking for in order to understand the characteristics in those patient populations. So, the progress is that we have the study ongoing. We have 2 active sites. We did do some tweaking when I arrived at the company. We modified the protocol to make it simpler and easier and a little bit more straightforward. So, there was a little bit of a delay in sort of the changes that occurred there. But we are on track, and our expectation is still that we will have data for the end of Phase II meeting.

Got it. And then just on the DDI study, could you just comment on why that's a requirement considering that you had background antifibrotic use in your prior IPF studies?

Yes. So that's a great question. And I think it really -- this is one of those Phase I studies that you just need to characterize it. This is more about the metabolic -- potential for metabolic PK drug interactions. Our drug is metabolized through primarily CYP liver enzymes. Antifibrotics will be used in patients pirfenidone and nintedanib. It's really a check-the-box activity based on the metabolic fate or the way the drugs are metabolized for pirfenidone and nintedanib. There's no expected drug-drug interaction.

But the reason you do these studies, especially before you get to Phase III is you want to see if when you put these drugs together, if there's any change in the pharmacokinetics of our drug or the other drugs, which may impact the overall efficacy of the compounds. And we know that there have been some data out there where folks found out in Phase III that, there was a pharmacokinetic interaction that did have a direct effect on efficacy for at least one of the doses. So, this is a study that was on the books because patients with IPF will be on these drugs, and it's pretty much an activity that the FDA was expecting, so it was planned for us.

The next question comes from Jason Dorr of Oppenheimer.

Jason here standing in for Leland Gershell. One or 2 questions from us, first of which is going to be, how are you thinking about the key questions to iron out in the upcoming FDA meeting as your team plans for Haduvio's Phase III trial in IPF cough? And regarding one of your other indications, what color can you provide on the soon-to-start trial in non-IPF ILD chronic cough?

Jim, you're the guy. Go ahead.

Happy to talk about both of those things. So, end of Phase II meeting is a very important meeting. It's also a very routine meeting for anybody that's going to advance clinical development. The key thing that we'll be bringing to the FDA at the end of Phase II meeting is the data we've collected to date, especially data from CORAL, which was our definitive dose-ranging study. It's about the adequacy of where we are in our program, how we establish the doses that we want to use and primarily to talk about the Phase III program, the readiness to be into Phase III, the specifics of the protocol. Typically, the protocol for the Phase III is submitted as part of the briefing document.

So, we'll definitely have a lot of discussion about the Phase III, get their buy-in on that, as well as, as we look forward towards NDA, the other anticipated trials that we may we or the FDA may decide that we need to do in order to have a sufficient package for registration purposes. So, things like these DDI studies that we're doing will all be part of that package. So, we'll have that conversation with the FDA then as well.

And one of the other things that's important to get out of the end of Phase II meeting is what the expectation is on the size of the safety database, the duration of the data that is included in the safety database. And as we've been expecting all along and talking about some kind of a long-term extension trial beyond our Phase III that will satisfy the FDA's requirements for longer-term exposure than what we need to do to show the preliminary safety and efficacy. So that answers that part of the question. I'll pause there if you have any other question on that.

On the non-IPF-ILD, we've had a lot of great interactions with pulmonologists and KOLs in this space. As you know, IPF is an interstitial lung disease. It's a very well-defined population. As you heard from us before, there are a lot of other patient groups who have interstitial lung disease, but not IPF. So, people with rheumatoid arthritis or Sjogren's or systemic sclerosis. So, we'll be looking at that other population defined by a certain amount of lung fibrosis as well as minimum cough. So, we'll be really looking at that part of the population. We expect the endpoints and everything will be the same as in the IPF because it is a continuum with the IPF population, with the underlying lung fibrosis. So, I think we have a pretty good handle based on our conversations with the experts here on what we need to do for the conduct of that study. So, it really is expanding the patient base.

And Jim, I think I would just add because we -- I think before, I talked about this next study as being sort of a Phase IIa crossover. I think after going through all the IPF data and discussing it with the KOLs, this drug works in cough. I think the whole proof of concept, does this drug work here? Nobody thought that added a lot of value. So, we've evolved our thinking to think about doing something that's definitely a parallel arm design and maybe sort of move this program along faster.

So, we want to align with the agency on that plan and how we might lean in on that and sort of have it meet up with our IPF program somewhere along the way. So, I would say a little bit of evolution in our thinking as we've gotten all the data.

The next question comes from Annabel Samimy of Stifel.

I just want to follow up on that last point regarding the parallel design for the non-IPF-ILD study. So, I couldn't help but remember some of the KOLs stating that the ILD patients or non-IPF patients rather have a pretty much of a similar disease progression as well as a fibrotic mechanism or interstitial lung disease mechanism to their cough. So, when you talk about a parallel design, is it possibly maybe even some kind of basket trial and I guess, sticking with a Phase II without having to move rapidly into -- or move into a Phase III to get a label expansion? Is it just going to be showing some level of proof that it works given that this seems to be a general -- have such a general mechanism that it works across all cough indications. So, I guess that's the first convoluted question I have.

Question du jour. We've been debating that in here. Go ahead, Jim.

Annabel, yes, the answer is yes. So yes, I would characterize it less as a basket trial and more as there's going to be a minimum criteria for coming in that will allow these patients that may have very different kinds of comorbidities to be enrolled in the trial. So, your point is that, there is a commonality here on the fibrosis and in some cases, even the progression.

So, we'll be maybe a little bit more opened up and less specific on certain types of comorbid conditions coming in. So that's on the basic pool. So again, I think we've gotten broader in our thinking in that regard with the help of the experts, who feel like this is like the fibrosis is really the key criteria here.

And cough.

And the cough and obviously, the cough. So, the parallel group or parallel arm design study, think of what we learned from CORAL. And as Jen said, it's really good to jump to something like that now. We don't really need to do the proof of concept. I think we all are believers there. I think the key is that we will be able to look at this initial Phase II type study digest the results and as appropriate and with further conversations with FDA, maybe even meld it into our IPF program as we move things in parallel down the road. I think the important point here is that things will be moving in parallel. And when there's opportunity and the right kind of data sets, we will be able to have those discussions on melding.

Okay. Got it. Got it. Okay. And then just on IPF, I guess, I'm still pretty impressed with the tolerability and the low discontinuation rates that you have. And I guess, combine that with the strong quality of life scores that you had. I guess, my question now is, now that you've dug into this data and you've really gotten a chance to characterize some of these adverse events and how they were primarily on initiation regardless of dose. Is there anything more that you can say about this? And do you really think you need to actually make any changes here? Because it seems like everything lined up pretty nicely for you on the tolerability side and on the quality of life side. So, it goes well together. So maybe you can just comment on that.

Yes. I mean, we were so happy with the CORAL data with the outcome of that, the consistency of the findings on the primary and the key secondary and the other secondary endpoints. So, I think we learned a lot. There's no real changes that we're thinking about going forward. Obviously, we'll be discussing the specifics of the Phase III design, including the dose selection with the FDA at the end of Phase II meeting. So, I think we learned so much from the CORAL study. We're in really good shape for how we plan things going forward.

Next question comes from Josh Schimmer of Cantor Fitzgerald.

This is Alexa Deemer on for Josh Schimmer, and congrats on a great quarter. So, my question is with more of the complete data for CORAL now available, how are you thinking about which dose or doses to bring forward in the Phase III study?

Great question. So, we know that when we look at our overall data sets that the 54-milligram BID dose is really a sweet spot dose. It really performed quite well. It really had broad impact across our primary and secondary endpoints. So, we know that as we think about this, the 54-milligram BID dose is going to be a key dose that we bring forward.

Obviously, there will be a placebo control. We will be discussing with FDA our dose selection rationale. So, we can't really talk about all the specifics there. But I think you can anticipate that 54 is going to be a key dose bringing forward.

The next question comes from Serge Belanger of Needham & Company.

I believe you highlighted the full results of the CORAL trial that you received, I guess, over the last month. Can you put -- maybe provide a little more context around the LCQ data, how it relates to the primary endpoint? And are there other secondary endpoints that we will see at medical meetings or in publications in the future?

Sure. So, the Leicester Cough Questionnaire is a really widely used quality life questionnaire. We reported previously that we have very significant findings at the total assessment. When we look at the domain scores of physical, psychological and social domains, especially like I mentioned the 54 dose, we see very, very strong effects on those domains. So, these are looking at the impact of the -- of cough on their physical domain, social aspects of their life, psychological aspects of their life, and we see very clear significant findings, again, focusing on the 54 dose, very, very clear findings there.

So I think that really helps. It complements the objective cough data that we have. So, this is objective cough is objective cough is measured with an instrument. This is now the patient opining on how their life has been changed, their quality of life on these specific domains and rolling up into this total score. So, I think it complements and puts the patient perspective in the light of the reduction in cough frequency.

So that's a very, very -- the reason we highlight that is because it's a very common type of assessment tool, and I think a very important one when we look at quality of life. We have looked at the other patient-reported outcome measures that we'll talk about at future meetings, patient global impressions, clinician global impressions, and we talked about the cough severity scores. So, there will be lots of secondary endpoint patient-reported outcome data to come at further meetings.

I just wanted to add something to what Jim was saying. The LCQ is a really important thing in terms of reimbursement and value, painting that overall picture in addition to the primary endpoint and the key secondary endpoints. So I think Jennifer said upfront, the linkage also here is if you look at the U.S. Pulmonary Fibrosis Foundation Registry, there was a strong link and correlation between baseline LCQ and impact on health outcomes. Now that will be seen over a much longer period of time. And I think that's something that we'll look at as we go to a pivotal program. How does this impact things like respiratory hospitalization and mortality.

And maybe a non-Jim question for Lisa. Should we expect OpEx to remain relatively flat from 2Q levels? For the remainder of the year until some of these larger trials get underway in 2026?

Yes, that's right, Serge.

The next question comes from Deb Chatterjee of JonesTrading.

So I had one question on RCC. So based on GSK's latest guidance, it seems that the KALM-2 will now read out potentially second half of 2026 with KALM-1 data coming together as a bundle. So, I was just curious, are you aware of any particular enrollment criteria related, maybe delays? What is actually the headwind for the trial? And are there any implications for the RCC trial you're planning? And I have a quick follow-up.

So this is Farrell. I can talk about just what we know. I mean we don't really comment on competitive reasons. We don't have any insight into what's causing some of those delays. What we know is when we look at our opportunity within RCC, we have the potential to be best-in-class in that indication. And I think that's the difference in approach that we're taking of going after a treatment-resistant population, those who failed other therapies. There's still a large patient opportunity there.

Yes. And I would just add, we would have loved to have seen their data before we fired off on our trial, but we're not going to hold up and wait for it. So, I think at this point, with their data sort of slipping back, we're going to be ready to go before that. So, it's going to have no impact on our program.

No impact at all. And I think the strength of the data that we had from the RIVER trial, I think will have really positive impact on our ability to run the next trial as well. I think that that's also a thing that that not only physicians but the patients pay attention to as well. So, I don't anticipate any problem. I don't know what the delays are related to there. I know, they're running a big global trial, but our next trial is going to be dose ranging coming off of really solid data. That will go a long way.

Very helpful. And a quick follow-up. This is like related to IPF. So, you mentioned the drug-drug interactions with nintedanib and pirfenidone. Any plans of checking for drug like interactions with nerandomilast?

No. There will be some other drug-drug interaction studies that, again, relate to mechanism of metabolism. Those are very standard. They've been on our list of things to do before the NDA. But no, I think those are the 2 antifibrotics that we'll be focused on.

Next question comes from Ryan Deschner of Raymond James.

Have there been any other interesting trends or post-hoc analyses coming from CORAL RIVER that have caused your perspective on dosing to evolve in either indication? And can you also give us any additional detail on what specifically you're planning to present at ERS later this year?

We've done a very deep dive on analysis of our dose effects. We've absolutely I think, concluded that 54 is a very key dose for us. I don't want to get ahead of our skis on talking about how we might approach another dose in the trial until we have that conversation with the FDA. But I think you can really see based on the -- all the analysis that we've done internally and had discussions with some experts and statisticians that 54 is going to be an anchor dose for us.

Yes. And otherwise, Jim, I would just add, no surprises, right? AEs came on early. They tend to dissipate quickly. I mean it's the same personality that we've seen in every sort of trial.

And obviously, 27 will be used at a minimum as a titration dose.

Yes, I think just robust. As far as your question, Ryan, on presenting at ERS, we have 2 abstracts that have been accepted on RCC. We're going to be putting our IPF data in at CHEST because we wanted that presented in the U.S., which is in October in Chicago. So those are the 2 medical meetings that our data will be hopefully presented at. We know we've been accepted at ERS for RCC, but we don't know about CHEST yet.

Excellent. Congrats on the progress.

The next question comes from Brandon Folkes of H.C. Wainwright.

Maybe just coming back to a bit of an old topic here. But understanding there's not really a commercial impact on the scheduling in the IPF patient population. Have you done any commercial work or have any thoughts on scheduling impact in the non- -- sorry, non-IPF ILD indications just in terms of prescribing habit?

Thanks, Brandon. This is Farrell. So, we've done some qual work within that space to talk to providers. When you look at the overall key prescriber in that area, it's still going to be that pulmonologist. And so it really is the call point to the pulmonologists where we don't see a sensitivity to the mechanism behind the prescribing. We're going back and testing an updated TPP based on the CORAL results. We'll test that across a broad range of potential patient types, but we don't anticipate an impact in non-IPF-ILD either.

Great. And maybe just one follow-up. Understanding what the respiratory depression study is about here. But if we see any anomalies unexpected on the negative side, is there any obligation in terms of submitting that to the DEA in terms of scheduling? Is there any precedent that we need to keep one eye on sort of the outlier event if we do see something in that data on scheduling? Or is that completely closed now?

I don't think that the respiratory safety study will have any direct impact on scheduling per se. I think it really is about just establishing and showing the characteristics that we're looking at in that study. I think scheduling is really going to be based on abuse liability and potential on that side.

The next question comes from Kaveri Pohlman of Clear Street.

As we move into the Phase III trials with longer follow-up than what you have for the Phase II, how are you planning to manage this placebo effect? And also, what challenges did you address in the Phase II that give you confidence going forward? And additionally, based on historical data and your own experience, are there any new hurdles you anticipate in the Phase III? I guess this is more like a remedial question. And another question I have is on -- as you're approaching Phase III, I would like to understand if there are any extra steps in terms of manufacturing for potential commercialization? And any updated thoughts on partnering for commercialization?

I can take the first…

We do all the development...

I can take the first...

Okay.

Thank you for the question.

I don’t know why we limit you to one question..

No worries. So as far as the Phase III goes, I think we learned so much in the program so far. I think CORAL was a real testing ground, proving ground for us in terms of the parallel group design. We learned a lot from that study. And I think some of the things that we learned was the rapid onset of effect. Really, we saw the drug effect, the efficacy coming in by that 2-week time point, things pretty much stabilized from that point on.

So, I think we don't anticipate any changes beyond that. So, in the course of that overall 6-week study, we saw that efficacy stabilized over from weeks 2 to 4. I think that was fine. We didn't see anything new really popping up later on in the dosing weeks in terms of safety. So, I don't think we need to anticipate that.

The placebo effect, I'm not sure that we really have a placebo effect. We had, I think, a well-controlled trial. I think, obviously, going bigger trials is something we always have to watch for, but we had a very large effect size. So, I don't think we're anticipating any issues there in terms of trying to control that placebo effect when we have the kinds of delta that we have right now.

I don't think we're going to see any new hurdles as we look forward into longer-term dosing trials. I think we've really tested that here. We don't see anything with the history of opioids where things really pop up later. Usually, things pop up earlier. I think we saw that in our trial. I think we saw that during the titration phase where we did see the adverse events that pretty much dissipated during that titration phase and really did not come back as we maintained our dose at the -- even at the 108 level.

So, I don't think we have any surprises on the horizon. I think we're really good there. Just a quick response to your manufacturing question. We know how to make the drug. We know how to supply the drug for bigger trials. We've been in Europe, and we've been in other places. We know how to get the drug distributed. So, no issues there on the Phase III front. I mean this is -- we've got an experienced team here that have run large trials before, and we've already been to a lot of places. I don't anticipate any problems with that. So -- that's as far as I remember.

That was impressive. I'll take the partnering question. So, that's something that Farrell and I always spend time on, obviously. I think where partnering is probably most relevant for us is in Europe or Japan. In the U.S., Farrell is kind of all steam ahead on how this gets commercialized here. I think if somebody wanted to have those rights in the U.S., they'd have to buy the company.

So really no change for us. We wouldn't look to probably partner this now in Europe or Japan, maybe Japan, I guess, but not Europe. We're just really focused on our Phase III program, how we get to the end, get good data and obviously are in relevant conversations with strategics as it makes sense for the company.

Congratulations.

The next question comes from Mayank Mamtani from B. Riley.

Could you please touch on the dose levels you're exploring in the 2 Phase I trials? And also, curious if this dose-finding work between IPF chronic cough and RCC helps you with the IP strategy? And just maybe my follow-up on the CHEST presentation for the IPF data, would you have any FVC data there maybe segmented by background therapy or without background therapy?

I'll take the CHEST thing, Jim, and then you can take -- I think I got the other ones. The CHEST, Mayank, is really going to be a lot of the primary data we've already disclosed in IPF. FVC, we don't plan to publish. As we've said sort of consistently, it's a safety parameter, but it's not -- it was too short of a study to really get at anything there. So I don't want to get anyone excited that there's something new that we're going to put out there. It will be really around our primary data.

I think, Jim, I can also take the IP question, which was I mean we're always looking for in any study we run after every study we complete, we meet with our IP lawyers, review all the data and look for anything that might end up in the label that we can file claims around dosing or whatever. So that's an ongoing activity here. I think we'll have to wait and see the data if there was something that was surprising or nonobvious, and we'll file dosing claims around that. So that is an ongoing activity.

The Phase I studies are single dose strength studies that we compare -- I'm sorry, the TIDAL study is a dose escalation up to our -- the top dose that we are using in that study. And then the EI study is against pirfenidone and nintedanib under various dosing regimens against the single dose strength of nalbuphine.

I am not showing any further questions. This concludes our question-and-answer session. I would like to turn the conference call back over to Jennifer Good for closing remarks.

We appreciate you joining us for today's call. Enjoy the rest of the summer, and we are available after the call for any follow-up questions. Just e-mail Lisa or myself, and we will get you on the schedule. Thank you.

The conference call has now concluded. Thank you for attending today's presentation.

Good morning, and welcome to the Trevi Therapeutics webcast presenting the topline results from the Phase IIb CORAL trial of Haduvio for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis. [Operator Instructions] Please note this event is being recorded.

Various remarks that management makes during this conference call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent quarterly report on Form 10-Q.

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so even if its views change.

I would now like to turn the webcast over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good morning. Thank you for joining us to review these exciting positive topline results from our CORAL Phase IIb trial of Haduvio in patients with IPF chronic cough.

I feel like we are reporting the final piece of the data trifecta that has occurred at Trevi over the past 6 months with positive results in 3 studies, human abuse potential, refractory chronic cough and now in our lead program, treating chronic cough and IPF. Times like these make a fun to work in biotech. We are excited to share the robust results from this study. And following the presentation, we will open it up for Q&A.

Joining me today on this call are my Trevi colleagues, Dr. James Cassella, Trevi's Chief Development Officer; and Farrell Simon, Trevi's Chief Commercial Officer.

We are also joined by Professor Phil Molyneaux. Professor Molyneaux is a leading key opinion leader in the IPF ILD and chronic cough space and a Professor of Respiratory Medicine at the Royal Brompton Hospital in London. He runs a multidisciplinary research team focusing on interstitial lung disease and pulmonary fibrosis. He was a principal investigator for our CORAL trial and the U.K. trial lead investigator and has continued to provide his deep expertise to Trevi's development program in IPF chronic cough. Thank you, Phil, for joining us.

Before diving into the results shown in graphs and P values, I wanted to take a step back and bring the voice of the patient to the forefront. When we talk to patients about the management of their IPF, we continually hear the challenges these patients face in controlling their cough. IPF is a terminal disease and chronic cough can impact nearly every aspect of these patients' daily life. You can see on this slide some of their direct quotes. The challenge for these patients is there is -- there are no approved therapy for the cough and the available antifibrotics do not improve their cough or quality of life. Even in the recent data presented on the new antifibrotic by BI put out ATS, we once again saw that patients with IPF and PPF saw no benefit in their cough, consistent with the 2 antifibrotics on the market. These quotes remind us of the high remaining unmet need that patients with IPF face when experiencing chronic cough, and how we must do better to innovate to improve on this key comorbidity that is debilitating and disruptive to patients' day-to-day lives.

A quick snapshot of the disease of IPF and the role chronic cough plays. We estimate there are currently about 140,000 patients with IPF in the U.S. and the number continues to grow due to increased incidence of IPF earlier diagnosis and increased use of antifibrotics extending the lives of these patients. Up to 80% of IPF patients have reported a chronic cough and have an average life expectancy of 3 to 5 years from diagnosis. There are no FDA-approved therapies for the treatment of chronic cough in patients with IPF.

On the right-hand side of this slide, you can see in a large U.S. patient registry study that better cough quality of life of patients is correlated with better outcomes in respiratory hospitalizations and death, and there is some evidence that cough may be profibrotic in these patients.

Okay. Now for the -- slide. I will review at a high level the trial results before Jim provides more detail and color. I want to remind everyone that these are the first positive results in a Phase IIb parallel group trial for the treatment of chronic cough in patients with IPF. No other program has made it this far. The results are clear in this trial with a dose-related response on the primary endpoint and the secondary endpoint aligning.

First, as you can see with our primary endpoint, we saw a dose-related effect on the relative change at 6 weeks from baseline in 24-hour cough frequency ranging from 60% at the high dose group to 48% at the low dose group. All 3 doses were statistically significant and the highest dose group of 100 milligrams BID translated into a 43% placebo-adjusted difference. The objective cough data were supported by the patient reported outcomes, including topline data, which related to both the patient's perception of cough frequency and severity.

In the CORAL trial, we consistently saw the rapid onset and broad effect of Haduvio. Based on the objective 24-hour cough monitor, cough frequency was reduced as early as week 2, which was the first time point measured. We also saw a majority of patients on Haduvio achieve a 50% or greater reduction in their cough frequency. This is consistent with what we have seen in our previous trials across chronic cough indications and confirms the strength of the data in this parallel arm design.

I was also very pleased to see that overall discontinuations were low and were pretty evenly split between placebo and drug with placebo being 5% and the Haduvio dose group in total being 5.6%. As the drug advances in development, we have been able to optimize the titration schedule and educate the patient to better move through the early tolerability AEs, which are primarily grade 1 and 2 events. It also helps when the cough response is so dramatic early on.

Jim will review the top treatment-emergent AEs, but the adverse event profile in this study was consistent with other studies we've conducted with Haduvio.

I'll close my upfront comments reminding everyone of our unique mechanism of action for Haduvio. Haduvio targets a cough reflex arc both centrally and peripherally as a kappa agonist and mu antagonist, which are opioid receptors that play a key role in controlling chronic off. We believe it is engagement of the mechanism along the full cough reflex arc from the lung to the spinal cord up to the brain that provides the robust response you see in these results.

I'll now turn it over to Jim.

Thanks, Jennifer. Good morning.

I am very happy to share with you today the findings from CORAL, our Phase IIb trial investigating the effect of NAL ER Haduvio in patients with IPF who are experiencing chronic cough. The results show significant improvement in both objective and subjective measurements of cough frequency and cough severity in these patients following treatment with NAL ER. The parallel group design trial replicates and expands on the findings from CANAL, our previously reported Phase IIa crossover design study, which showed the potential benefit of NAL ER on cough in patients with IPF. Since the Phase III trials will utilize the parallel group design, the results from CORAL will directly guide power and considerations and design efficiency for the Phase III program.

Let me review the study design and objectives with you, and then I will go into more detail on the end points. This was a randomized, placebo-controlled double blind parallel group dose-ranging study assessing 3 doses of NAL ER and placebo on cough in patients with IPF. The 3 doses of NAL ER were 27 milligrams twice daily, 54 milligrams twice daily and 108 milligrams twice daily. Going forward, twice daily dosing will be referred to as BID.

For entry into the study, patients were required to have a diagnosis of IPF and a history of chronic cough that lasted at least 8 weeks prior to screening. Also, in order to ensure a meaningful level of cough severity for entry into the trial, patients had to have a score of at least 4 on a scale of 0 to 10 and on a cough severity patient-reported outcome scale at both screening and baseline time points. Since these are patients with significant lung disease, background antifibrotic therapy was allowed in the trial. The primary endpoint of the study was the relative change from baseline in 24-hour cough frequency reported as cough per hour for NAL ER compared with placebo at week 6.

Secondary endpoints available for the topline data analysis included 24-hour cough frequency responder analysis as well as patient-reported outcomes for cough severity and cough frequency. The study design included an initial 2-week dose titration period followed by a 4-week fixed-dose treatment period. All patients initiated dosing at 27 milligrams. Titration to 54 milligrams BID occurred at day 7 for the 54-milligram BID and the 108-milligram BID dose groups and the final titration for the 108-milligram BID dose group occurred on day 14.

Dosing was fixed for all dose groups starting on day 14. Cough was measured by the injective cough monitor using the VitaloJAK device at baseline, week 0 and at weeks 2, 4 and 6. The primary efficacy endpoint was the relative change from baseline and the 24-hour frequency compared to placebo at week 6. Patient reported outcomes were captured as secondary end points. There was a total of 165 patients randomized into the trial and the baseline characteristics of the patients are in line with our previous IPF cough trial and what we would expect from patients with IPF.

The study population was approximately 3/4 male with an average age of around 70 and a mean 24-hour cough frequency between 24 and 31 cough per hour ranging across the dose groups. This translates to approximately 600 to 750 coughs per day. Patients had reported that, on average, they experienced chronic cough for a little over 4 years. About 80% of the patients were taking an antifibrotic drug for the treatment of their IPF. The primary efficacy endpoint of relative change in 24-hour cough frequency assessed by objective cough monitoring at week 6 was analyzed by a mixed-effects repeated model, MMRM. The primary analysis was conducted on a modified intent-to-treat population, MITP, which consisted of all subjects who were randomized and received at least 1 dose of study drug or placebo. One patient from the placebo group was an extreme outlier for their effective cough data at week 6 and was excluded from the primary efficacy analysis.

Inclusion in this patient would have resulted in an increased cough frequency from baseline in the placebo group, which would result in a much greater placebo-adjusted difference for NAL ER. So we determined with our statisticians that it was most appropriate to exclude this patient from the analysis for the 24-hour cough frequency. NAL ER showed a dose-related reduction from baseline cough frequency compared with placebo with approximately 48% reduction for 27 milligrams BID, 53% reduction at the 54-milligram BID and 60% reduction at the 108-milligram BID compared to a 17% reduction for placebo.

The 108-milligram BID dose represents a 43% placebo-adjusted difference. All the NAL ER differences and 24-hour cough frequency from placebo were statistically significant with P values ranging from less than 0.01 for the 270-milligram BID dose group in less than 0.0001 for the 54-milligram and 108-milligram BID dose groups.

This slide shows the reduction in cough frequency by week and shows a rapid reduction in cough frequency for NAL ER across all doses, starting with the first post baseline objective office spend at week 2 of dosing. The magnitude of the reduction from week 2 through the end of the study is steady and persistent, indicating a near maximum once the cough response in NAL ER is evident. Note that statistical analysis depending on these data and is not currently available for these topline results.

The next slide shows the comparison of NAL ER with placebo using a responder analysis assessing response rates at different levels of cough reductions. It is widely believed that a 30% reduction from baseline and cough frequency represents a clinically meaningful improvement. As you can see, at least 75% of the patients treated with NAL ER achieved this clinically meaningful level of cough reduction, which was statistically significant from placebo for all dose groups. As we assess a more stringent threshold of 50% change from baseline, approximately 60% to 65% of the patients on NAL ER achieved this response level.

All the NAL ER dose groups at this threshold were statistically different from placebo as well. And for the very high bar of 75% reduction in 24-hour cough frequency, we see a dose-related response with the 54-milligram BID and 108-milligram BID dose groups being significantly different from the 5% placebo response rate. 37% and 43% of the patients in the 54-milligram BID and 108-milligram BID dose groups, respectively, achieved this meaningful 75% reduction of cough frequency.

We are also able to share with you today 2 of the patient-reported outcome measures that were assessed in the trial and plan for this topline data readout. Other patient-reported measures will be available when full data analysis completed in the near future. The patient reported cough frequency question asked patients over the past 24 hours, how often did you cough. This scale is scored with the patient choosing responses on a 5-point scale ranging from 0 equals not at all to a 4 equals almost constantly.

The right panel of this slide shows the separation of responses over time for all the NAL ER dose groups compared with placebo. Statistical analyses across all the time points for these cough frequency values are pending and not yet available. However, we do know that at week 6, the 54-milligram BID and the 108-milligram BID dose groups were significantly different from placebo, but the 27-milligram dose group were not.

The left panel shows the relative change from baseline at week 6 for the same patient reported cough frequency scale. The 54-milligram BID and the 108-milligram BID dose groups differed significantly from placebo with approximately 40% relative change from baseline compared to 23% for placebo. For the patient-reported cough severity question, Patients were asked to indicate the severity of cough they experienced over the last 24 hours on an 11-point scale with 0 equals no cough and 10 equals worst possible cough. Patients had an average score of approximately 6 at baseline.

The 54-milligram BID and the 108-milligram BID dose group showed a 3-point or greater improvement at week 6 with a statistically significant difference from the placebo group. The 27-milligram dose group showed numerical differences from placebo that were not statistically significant. So for the PROs assessed to date, we find consistent and robust patient perceptions of reduced cough severity and cough frequency, which corroborate and complement the reductions observed with objective cough monitoring.

Let's turn our attention to the safety data from the trial. There were no deaths reported in the trial and the serious adverse events that occurred were at a higher rate in the placebo group than in the combined NAL ER dose groups. Discontinuation due to adverse events were similarly distributed in the placebo and active dose groups, which we were very pleased to see.

This slide shows the overview of the state data, and as previously mentioned, there were 4 SAEs in the placebo group and 2 across NAL groups. 5% of the patients on placebo discontinued due to adverse events and 5.6% of the patients of any dose group of NAL ER discontinued due to adverse events. The most common adverse events leading to discontinuation were headache, nausea and vomiting. These findings are consistent with our experience with NAL ER in our previous cough trials.

This slide displays the common adverse events, defined as greater than or equal 10% in the total active group reported in the trial and include nausea, vomiting, constipation, dizziness, headache, fatigue, somnolence and dry mouth. The majority of the AEs reported were mild to moderate in severity. There appears to be some dose-related increase in some CNS and GI adverse events. But for the most part, the adverse events reported in the trial are typical for this class of drug and are consistent with those found in other trials conducted with NAL ER.

In summary, NAL ER achieved the primary endpoint in this Phase IIb study with statistically significant and dose-related reduction and 24-hour cough frequency. This is the first parallel group study to demonstrate a significant reduction in cough frequency in patients with IPF. Patient-reported outcomes and other secondary endpoints assessed in this topline data analysis showed significant results consistently across the 54-milligram and 108-milligram doses and support our belief in the broad effect of NAL ER on cough.

Overall safety and the NAL ER dose groups is consistent with our previous cough studies and are consistent with this class of drug. We are very pleased with the outcomes of this trial and look forward to discussions with the FDA in further exploring the potential of NAL ER to help patients with IPF, who are experiencing chronic cough.

I will now turn it back over to Jennifer.

Thanks, Jim.

As we've looked at the competitive landscape in IPF chronic cough, we continue to believe that we have the potential to be best-in-class and first-in-class. With these parallel arm results supporting the efficacy and safety profile of Haduvio in patients with IPF chronic cough, we move a step closer to making this therapy available to patients. We are planning for this indication to lead our commercial strategy with high unmet need in these patients and no approved therapies, it sets up very favorable specialty commercial dynamics in terms of pricing and field force footprint due to a focused call point in pulmonologists and ILD care centers.

From our research, we would expect a rapid uptake in physician prescribing as they don't have any safe and effective therapies that work across patient types for IPF chronic cough. You can see in the middle of this slide the various off-label treatments that are being tried now, none of which work that well. So we believe this is a strong commercial opportunity that can be executed in a highly efficient manner. We have also been thinking about the equally high unmet need among patients with non-IPF ILD chronic cough. IPF sits in the broader category of interstitial lung diseases and represents the largest individual indication.

The remaining non-IPF ILD category encompasses over 200 indications and shares a common lung fibrosis with IPS. And because of that fibrosis, these patients have a difficult-to-treat by dry chronic cough. With the positive CORAL results announced today, we are finalizing a protocol to stay Haduvio for the treatment of chronic cough in patients with non-IPF ILD in a basket study and expect to move forward and initiate a study by the end of this year. Our current timelines project these data in late 2026. We will provide more formal guidance around this trial when it is initiated, but we are excited to move into this patient group and potentially double the market size of this opportunity broadly in interstitial lung diseases.

So in closing, chronic cough represents a high unmet disease burden in both IPF and other interstitial lung diseases as well as refractory chronic cough and Haduvio is the only investigational therapy to have been shown to work both IPF patients with chronic cough and RCC patients. There are no approved therapies for these indications in the U.S. and a limited development pipeline. This CORAL Phase IIb trial confirms the strong results we previously saw in the crossover designs. We conducted in both chronic cough IPF and RCC, setting us up nicely to design and execute our Phase III program.

Finally, our team has been preparing in the background for positive results, and we are ready to move quickly into the next phases of development for each of our programs. Here is a quick list of the catalyst pathway over the next 18 months at Trevi. In the second half of this year, we plan to request an end of Phase II meeting with the FDA to align on the Phase III program in IPF chronic cough. Also in the second half of this year, we plan to initiate a trial in patients with non-IPF ILD chronic cough.

In the first half of 2026, we are preparing to initiate the chronic cough Phase III program as well as initiate the Phase IIb RCC trial. In the second half of next year, our timelines project topline data for the non-IPF ILD chronic cough trial. It Is an aggressive but focused plan. We know how to run these trials. They are not large and mostly replicate what we have done to date. We feel confident in our ability to execute, and believe, we have an opportunity to develop a therapy that is very meaningful to patients that are suffering from the disease of chronic cough.

With that, Jim and I are finished with our prepared remarks, and now we'll open it up for questions for our broader team.

Operator, please go ahead and queue the questions.

While the operator is queuing the questions, I would like to ask Dr. Molyneaux to make a few comments about the unmet need of cough he sees in his patients as well as any thoughts on the data. And Drew, I realized I cut off your instruction. So give your instructions and then Phil, maybe you could make a few comments.

[Operator Instructions]

And again, back to you, Mr. Molyneaux for your comments, sir.

Thank you very much. And firstly, congratulations, Jennifer to you and the whole team at Trevi. You really outdriven it forward from the first phase, standing into this. What is the first positive Phase IIb study. We can't really overlook that. There have been a number of compounds that have tried to get to this stage and all failed, and this is a really remarkable achievement. I mean if someone who looks after patients and these patients every day, cough is a massive problem, is what the majority of our patients talk about. We historically think about breathlessness, but when you actually speak with patients, they can slow down, they can stop, they can pause none of that helps them with our cough.

And cough is a significant problem. Probably 80% to 85% of our patients will report cough, and we know that if you have cough at the time of diagnosis, that's going to plague you for the rest of your disease trajectory. It gives people a worse quality of life. It causes them to stop exercising. It causes them to stop going out. It becomes socially isolating. Post-COVID, cough has a stigma like nothing else. And the patients will often tell me that they can't go out to the house. They can't do the activities they once did, going to the cinema, going to the theater. It's just -- it just ruins everything for them. So with no effective treatments, they are really, really limited. So I really can't underplay the significance to the patients that cough brings.

I think when we look at these data, they really are fantastic. We see over 40% overall reduction against placebo. And that number is striking. But when you dive down Jim into the numbers of patients, who've got a 50% reduction and the 75% reduction. We're talking about 65% of patients getting an over 50% reduction in their cough count. That's a massive reduction. And 1/3 are getting over a 75% reduction in their cough counts. I mean these are numbers that are going to translate really well to patients, 50%, 75% reduction in cough counts. Not only that, these are reductions that are coming on in the first 2 weeks of therapy, patients are going to be able to see immediately the benefits of this drug.

And we talk about the benefits we have to talk about the potential side effects. I mean we've really well tolerated large numbers of patients here very few discontinuations. So even though we see the expected side effect profile that we know comes with nalbuphine ER, very few numbers of patients discontinued. And for me, that really speaks volumes to, one, how significant the problem is, two, how motivated the patients are, and three, how much they're willing to tolerate to get on to an effective therapy, which they just don't have at this moment in time.

So please, cough is a significant problem for our patients. It's a massive unmet need. And these are fantastic data, the first IIb -- positive IIb we've had. So I'm happy to help answer any questions at this point.

Thank you, Phil. That was helpful. We can go ahead and take questions now, Drew.

The first question comes from Faisal Khurshid with Leerink Partners.

So could you provide any initial thoughts on what the Phase III program could look like, including things like what doses are you thinking about moving forward? And also, do you think a 12-week end point would be possible for 1 of the Phase IIIs?

Faisel, Jim here. Thanks for the question. So these data really start our -- the firming of our plans now to the Phase III program. So thanks for raising that. I think the doses -- these are 3 effective doses. We clearly have some dose response here, especially when we look at the secondary end points I think we're going to make some decisions based on the full data set that we're going to see. The question of doses will really be on risk benefit at each of the doses, and we still have more data to come. So if we can stay tuned for that, we'll be able to give more guidance on that once we see the full complete data set over the next few weeks.

In terms of the trial duration, we've had a lot of discussions. We believe that something like a 12-week primary endpoint will be a reasonable one and probably one that will sit well with the regulators. But obviously, we need to have that meeting with the FDA, have that discussion on study design, duration, et cetera. So I think you're in the right ballpark when we think about 12 weeks. And once we get all the data in, assess the safety side and assess the efficacy side, we'll be able to make a good plan for the doses we want to bring in. I think it's fair to say we were thinking about 2 doses in the Phase III and a placebo.

The next question comes from Annabel Samimy with Stifel.

Congratulations on the data. So I know you're contemplating the go-forward dose for Phase III, and you talked about the risk-benefit factors. But what are those factors exactly to determine the go forward dose? It does look like there are more As for the 108-milligram versus the 54%, but you've mentioned in the past that more side effects are on initiation of treatment, and I can't help notice the lower-than-expected discontinuation rate. So what else should we be thinking about? And maybe for Dr. Molyneaux, you can describe the experiences in patients who were at the higher dose and whether you see any problem with.

Thanks, Annabel, I'll take the first part of that, and then I'll let Phil respond. So Annabel, I think you're right. I mean, we see things at the 108, we -- maybe we see a little flattening between 54 and 108. We clearly see less adverse events at the 27%. These are things that we need to put in the context of when did they occur? We don't have all the data yet to dig into time course of the adverse events. We know that traditionally, what we've seen here is that with the class of drug that we're talking about, things do usually come in earlier. I think we will be able to look at that. That's going to be a critical factor in weighing in. But I think it is a matter of is there additional benefit of going to the higher dose?

Are there advantages going to the lower dose. I'm sorry to put you off, but I do want to see all the data, and I think it's going to be really important. This is probably the most critical question we have going into the Phase III. I think we know how to run the study we'll do a lot of diligence on dose selection. Phil, I'll let you comment on the rest.

Thanks, Jim. And obviously, this is only the topline data, and we haven't been unblinded to individual patient level data to know exactly who is on what drug -- what dose, sorry. Our experience has been that this has been well tolerated as you can see by the topline data doing a number of ways to mitigate the potential side effects, which the study sites will have adopted. That can be translated into clinical practice. And I think the number of sites, the distribution of sites worldwide. This is not just a concentrated effort on 1 or 2 sites with a lot of extra support to get patients through things. This is a package that was put together that has been well executed and has meant that the dropout rates have been low.

I think it speaks to the -- perhaps the differences between patients who is refractory chronic cough, and I the different patient demographics, patient population and also the life expectancy and the significant impact that it has on these patients. I think you can look at the distribution of the side effects across the different doses. We can't really interpret anything as Jim says, until we know when it happens. But when patients are getting clear benefit within a 2-week period, I think that's speaking to them that they are then able to see that something is working.

And if you know that something is working at that point in time, and you've got a 75% reduction in your cough. And you're more likely to carry on taking the drug, especially if you've got a shortened life expectancy. So I think we have to look at the data that we have in front of us. It's a large patient population. It's geographically diverse across a multitude of sites. So we have to hope that that's the dropout rates we're going to see in this patient population going forward.

The next question comes from Leland Gershell with Oppenheimer.

Good to see the solid data set. A question for Dr. Molyneaux. I appreciate your reflections on the data and your commentary about the unmet need. Just wanted to hear your thoughts with respect to when in the IPF disease continuing this cough really become a problem do the baseline criteria accounts in patients in the oral trial do those represent the types of patients that you'd be using Haduvio, or would you actually look to use it perhaps in those who have milder cough, perhaps with an eye on the potential to improve disease progression.

Yes. So great question. There's probably 2 parts to that. So we know that patients that present with significant cough at the time of diagnosis continued to have significant cough. And that is a problem for them throughout the course of their disease. So we can identify these patients at the time of diagnosis. And if your patient has a significant cough, then you have a period of time to intervene on that. And there's no real reason to wait. These are patients with a life -- average life expectancy at 3.5 years to 5 years. So if you wait 12 to 18 months to start instigating therapy, you've already taken away 1/3 of that patient's remaining life and when you could have improved their quality of life.

So I see absolutely no point in delaying intervention. And certainly, our current practice with all of the non-approved and non-licensed therapies start as soon as we see a patient with significant cough. So I see no problem with this being instigated as soon as the patients see and cough is recognized as a significant problem. With respect to the alter disease trajectory, that is something that we simply don't know. The hypothesis being that cough induces stretch, induces TGF beta to release -- could drive the fibrotic process.

That is borne out in a number of mouse model, animal models, that paradigm of stretch TGF beta. We don't know what that means for lung function trajectory. And I think as we find effective therapies for patients then following them long term is going to be the only way of knowing that. So I personally look forward to getting an approved therapy that we can give patients in the long term and lock at the outcome because that is a potential that not only could it improve their quality of life, it could be disease modifying as well.

The next question comes from Serge Belanger with Needham & Company.

I'd also like to offer my congratulations on the data. A couple of questions for Dr. Molyneaux. First, can you talk about the nature of the cough in IPF patients and how it differs from cough you may have seen in patients with COPD and other lung diseases. And then the follow-up to that is, do the antifibrotic treatments have any impact on cough? And if they don't, how do you address the cough issue in IPF patients?

So great questions. IPF cough is more frequent than patients with COPD. So when we look at 24-hour cough count, we see an increase in COPD. We'll see a further step up in cough frequency in patients with IPF. So it's more -- the higher cough rates, not as high as in patients with refractory chronic cough, but certainly in IPF, it's higher than we see in COPD. The cough is slightly different as well, being that it's predominantly daytime, and there's hardly any nighttime cough events in patients with pulmonary fibrosis, which make it slightly different than other cough diseases or diseases where cough is a significant problem. So there are some differences.

Antifibrotic agents have not been shown robustly to have any effect on cough frequency. There have been a number of post-hoc exploratory projects and certainly, registry projects come with all the caveats that these pieces of work in tail where there's been a suggestion therapy with some of the antifibrotic agents have approved patient-reported outcomes. But the problem with some of the patient-reported outcomes is the symptom intertwined with things like impact on breathless and other aspects of quality of life that is hard to actually determine whether they've had a significant effect.

But there's certainly been no randomized controlled trials that have demonstrated any benefit of cough with the current antifibrotic therapists. So we're present, we're left with no recognized standard of care for cough in pulmonary fibrosis, which means that physician management is very varied from country to country. Some will use antidepressants, or someone who abitriptilib, gabapentin, others will use various opioids, but there is no real guideline or all standard dose for any of these things.

It's often a trial and error process, which will take some months. And the normal patient will see a number of escalations or attempted therapies over 18 to 24 months to try and find something that may help them. So as I've dialed -- rewind back to the average life expectancy of 3.5 to 4.5 years, you spent 2 years trying to find something that has a slight impact upon cough, then you've really wasted half of the patient's disease course when you could have had an effective therapy from day 1.

[Operator Instructions]

The next question comes from Deb Chatterji with Jones.

Congress on data. So I know there this is 2-week follow-up after you stopped losing in the study. I know that's mainly for safety, but would you be looking at cough as a safety endpoint in those 2 weeks?

We are not looking at cough in that time period. This is mostly a diligence follow-up just to make sure that there's no residual effects. So mostly, we're capturing adverse event data during that time.

Jim, as we go forward in our studies, we intend to measure coughs sort of over the safety time period of the year.

We will. So in an extension trial, we would clearly look at cough and other endpoints as well as safety once we go beyond our primary endpoint, if it is 12 weeks, and we have to go longer, we'll be looking at both safety and efficacy in that extension type trial.

The next question comes from Ryan Deschner with Raymond James.

Congrats on the data, and thanks for the question. Just curious on how you'd be looking at titration strategy in Phase III based on what you've learned so far in Phase IIb. And was the placebo that we're seeing here on the primary end point lower than you expected.

Thanks, Ryan. It's a really interesting question on the lead-in. I think based on our previous experience, and I expect that once we get into the the time course data for the adverse events, et cetera, here, we will probably have greater color on what we need to do to maybe increase some of our titration. We know that based on our previous experience that some of these adverse events that we see and even some of the early discontinuations may be to that initial exposure to the drug as opposed to even being dose dependent. So there are some strategies. I think we have a lower than what we expected discontinuation rate here.

We did have some strategies in the trial that -- in the CORAL trial right now, including the potential for going from twice a day to once a day, some mitigation strategies with other therapies to to fight the nausea or the vomiting. I think we're definitely going to take a very, very close look at if we need to maybe enhance our dosing strategy coming in the titration period. So those are all things on the table that we'll definitely take a look at.

And then he asked about placebo rate?

I -- we -- it was a big debate. I mean this is the first parallel group study. Let's just say that I think we all were very curious as to see how that placebo response. We've got to look in a parallel group study. We know in the RCC world, that was a little bit of land mine. We're very happy to see the response rate, the placebo response rate that we have. But I think it does it's credit to our investigators, the investigator site team the trial management that we were able to hold that kind of response rate down. I think maybe Phil has a comment on what he was thinking about for a placebo response rate, but I think we're very happy in the long run.

Thanks, Jim. I mean, I think the true answer is no one really knew what we were going to expect because only the data we have to base on the crossover studies, I think, and other Phase II studies, which have different delivery modalities so therefore, probably suffered from a higher placebo effect. So I think this is higher than some of the crossover studies we've seen lower than the other Phase II studies. And again, hopefully, given the size of the patient cohort, the geographical variability of the sites and a number of sites. This is probably a true reflection of what we're going to see in the Phase III study.

The next question comes from Mayank Mamtani with B. Riley Securities.

Congrats on the spectacular data. Could you touch on the importance of your lower dose clearing statsig at a 30% placebo-adjusted treatment effect, if this was a function of lower discontinuation rate higher sample size than you assumed? And if you're able to comment also on the sort of TRO information we may get, including at maybe some of the upcoming conferences. Then I have a quick follow-up.

So I mean, powering works on a number of assumptions coming in primarily your best estimates of effect size and standard deviation. And with that, you come up with an end for the trial. I think the lower discontinuation rate in the trial means that we had more in each of the doses than we had originally powered for. We did power for a 30% discontinuation rate. So obviously -- and that's overall rate. So when we look at our 10% rate, we still have more power there. So I think the effects that we see at the lower dose, the significance of that, even though it came in technically less than what we had power for, the assumptions of variability, this study was probably tighter in terms of variability than what we had expected.

So that allows for more cushion on the effect size. Also, we had more sub dose arm because of the lower discontinuation rate. So technically, we were overpowering our initial assumptions during the conditional powering calculations. So I think all those things together led us to the significant findings with a slightly lower-than-expected effect size for the lowest dose. In terms of the additional information that will be coming in, we will have more patient-reported outcome measures, the LCQ patient reported, patient global impression scores, et cetera. And as we continue to improve the cough count data, there might be some additional ad hocs that we might be able to put in there as well. So I think stay tuned for those, we will be looking at the meetings where we can meet deadlines for submitting our abstract. So we'll take those available once we were going to have.

Brief clarification of a prior question. Any chance you looked at FVC measure as part of the safety analysis or maybe in the ongoing respiratory physiology study, recognize you look at short-term effect, but obviously, wonder if antifibrotic information could come through, that could inform the scale scope of next Phase III program, particularly since the drug is being used in the context of background antifibrotic.

We do have FVC data at baseline at the end of the study. So we'll be able to report that out once we get all the data.

We haven't seen that yet.

We haven't seen that yet.

The next question comes from Brandon Folkes with H.C. Wainwright.

Maybe a sort of follow-up on an earlier question for Dr. Molyneaux. I know we've talked about the dosing a little bit, well I love to call you. And sort of how we're going to assess it on a risk reward and full data set. But I'd love to lean Dr. Molyneaux on the efficacy differences he's seen in the 50-milligram dose and the 106, how do you view those as potential real-world patient experience differences. Are you seeing what you think you need to see in the 54-milligram dose alone here and sort of just any insight into what you think the potential real-world benefit would be for these patients taking a 108 dose forward versus the 54, which seems very effective itself.

I'm happy to talk through that and probably Jim will come in and come halfway through. When you're looking at the -- as you look at the data as it evolves and the story evolves that Jim went through. And obviously, this is all caveat by saying this is just the topline data. We see a rapid improvement in cough counts in both the 54 and 108 and the 27 dose at 2 weeks, and we see these significant changes at 53% to 60% in the 54-milligram and 108-milligram. So at that point, it's going to come down to what we perceive is going to be the best dose with the best side effect profile.

I think we're in a position here where we've got 3 doses that were effective on cough counting. We see some differences and disconnect between that when we look at the patient reported outcomes, but we've only got some of the headline data in. I think once we get the rest of the PRO data, and we're able to deep down into some of the AE profiles to exactly when these events happened. We're going to be able to pick a clear dose strategy for the next Phase III going forward.

I think, Jim, do you want to comment at any point on that?

Phil, you hit it on nose, no cut offs, no hook.

I think it's just good news that essentially, there are multiple doses here that are having an effect on cough. So that gives the company option to pick, and it's going to give the patient option to pick as well.

And the last question will come from Kaveri Pohlman with Clear Street.

Congrats on the results. My question is mostly related to Slide 14. So if we look at the 2 doses 27 and 54, I believe, the effect kind of like goes up from week 4 to week 6, slightly. I believe similar pattern was seen in RCC data. Could you comment on that? And the placebo continues to go down. And -- so going forward for the Phase III trial, when you plan to do a longer follow-up, can you maybe tell us how you plan to control this placebo effect in those certain trials? And what issues you have addressed in the Phase II studies that give you confidence? And what other challenges do you expect from the Phase III studies?

Yes. It's a great question and good observation. I think we do see this rapid decrease at week 2. We probably -- these are -- remember, these are no longer with the subject types of variability here. I think we're going to expect to see some balance around these endpoints. I mean nothing bounces up above for the active dose group, nothing really bounces up above what we see in that first 2 weeks. So I don't really worry about loss of effect with the drug. But obviously, we'll see that when we go out longer.

Again, on the placebo response, we do see some decline over time. But it would be hard to imagine that, that's going to continue to drop down because it is a placebo group. And these patients -- this might be reflecting some so maybe some instability in the cough. We can try to control that a little bit better as we plan for the Phase III. So I think I'm not worried about these data. These are very strong effect, and I think that we will do our best to really keep placebo under control in the Phase III program. And at this point, we'll just take all the data into account and just plan for the price controls that we can.

Okay, thank you. In closing, I want to thank Jim and his team for the excellent trial of conduct. Of course, we also want to thank the trial sites and the patients for helping to move the research along in this important aspect of the disease. Thank you also to our shareholders for your financial support. Without that, these trials wouldn't be possible. You play an important role in advancing innovation and therapies to the patient. And for that, we are all grateful.

With that, we'll end the call, and the management team will be available throughout the day for any follow-up. Thank you.

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