Trevi Therapeutics, Inc. ($TRVI)

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.