In N.Y., we also have a lot of people online joining for the webcast. 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. I'm really happy to have you meet some of the depth in the company and around the field. I think you're gonna feel the energy of our group and the opportunity today as we work to move this drug closer to patients. I should reference our safe harbor. I shouldn't skip over that because we are gonna be talking a lot about the future, so obviously look at the risks around the company. I wanna 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. 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 James Cassella, our chief development officer, David 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 hates to stand up, 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. I just wanna recognize his huge scientific contribution not only to Trevi but to the field, Tom. 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. Stand up. I'm not gonna introduce every one of you. Definitely takes an army to get this done. We're 40 people strong. Really appreciate you guys coming. Thank you. Today, we're also joined by 2 of the top KOLs in our space. 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. We're super fortunate to have Dr. Peter Dicpinigaitis, 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, I'm gonna keep moving. With the exception of Dr. Maher's and Peter's section, the two KOLs, we're hoping you can hold questions till the end. We've left 20 minutes, 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.
You are the first group to get a preview, sneak preview of 2 of our videos which will run over the next 2 months. Let's start with the North Star in our industry. I know that's what we all focus on, the patient.
Chronic cough is one of those things that I wouldn't wish on my worst enemy.
Mentally and emotionally, it has robbed me of my life.
My cough can be so severe until the point where I have to vomit.
It hurts so bad and gives me a, you know, the migraine headache and all.
My chest hurts, my lungs hurt, my abdomen hurts, my sides hurt, my joints hurt.
If I go outside, and it's cold, that'll trigger a cough. If I go outside and it's humid, that'll trigger a cough.
If I were to paint a picture, it's almost like, I've got flames coming out of my mouth.
It's just humiliating to have to be in constant fear that I'll have a coughing fit at a very inconvenient time. No one should ever have to live like that.
It's not like I can do an inhaler, a nebulizer, anything like that and just make it go away. It's with me all the time and once it starts, it's hard to stop it.
A treatment for the chronic cough would mean the world to me.
A treatment for my chronic cough would give me so much peace back. Not just to me, but to so many of us living with the disease.
Any reduction in my chronic cough would give me life back, and it would make me feel like I can do anything. It would definitely make me feel whole again, and I haven't felt that in a long time.
Powerful and credit to Katie. She has a patient advisory panel which we circle back to often, and it's very helpful to us to always 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 this 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.
We're excited about that path forward. I'm gonna take you through the build of that vision. This sort of build that I show you, my team is gonna help go through each of those pillars in more detail today. First of all, it all starts with the drug, Haduvio, now nalbuphine ER. What's unique about our drug, we believe it's 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's gonna actually take you through a nice schematic of why that's important. It works along the whole cough reflex arc. We have 3 pillars for growth. One of the challenges we've had is this drug has worked in everything we've looked at it in. We wanted to really focus on the most severe cough conditions.
We're a small company and drive those over the finish line. We've always been IPF cough-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 and what we need to do. 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. Toby 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 II-B/III program later this year after meeting with the FDA.
Refractory chronic cough or RCC, we believe we have best-in-class phase IIa data. For those of you, many in the room followed BELLUS Health, which was acquired by GSK. They do have their data coming in the 3rd quarter. There's plenty of room for both of us here. There's a lot of patients with a lot of unmet needs. I don't think it changes at all what we're doing. These are very large, available markets. 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-$12 billion market, and Farrell's gonna 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, it's a $7 billion-$15 billion marketplace. No approved therapies, no competition. Refractory chronic cough is a very big market, $20+ billion, no FDA-approved therapies, 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, obviously we will look at it. I think that there has been lots of companies who have shown us you can do respiratory launches very well on your own, we are scaling the company to do that. We will be prepared for that moment to take this to market ourselves. Specialty pricing in this area.
Farrell shared some of that work. Specialty-sized sales force, 50-75 reps. This commercialization is very executable. Thank Verona, thank Insmed. They've got the playbook here. They did an excellent job at it. 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. I think you guys have seen as we've reported out our data, this has just been a nice build in the story. With that, I'm gonna turn it over to our Chief Development Officer and my good friend, Jim. Jim's been around the company a long time. Just quickly on Jim's background, Jim's a PhD neuroscientist, and he's been working in neuro area for, we'll say, 30-plus years.
Might even be another decade than that. Because of that, he brings a lot of tricks to the trade, I think, of dealing with drugs going to the CNS. We're super happy to have him.
Thank you. 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 it's never the right time of day to talk about neuro stuff. I just wanna touch a little bit on a few things today. It's probably a little different than some of you who've seen me before, where I talk more about clinical data. This is probably gonna be a little bit more eclectic. I wanna 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.
First of all, I want to touch on why nalbuphine seems to be the right choice for a drug to treat chronic cough. 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 a neurally mediated mechanism. As we look at what's going on here, you know, we know that, you, stimuli are entering the lung. They activate sensory nerve fibers. There are ion channels and receptors involved on the vagal sensory nerves that send signals up to the brain. Brain stem coordinates motor responses for cough. We have motor neurons triggering respiratory muscles to sort of provoke the coughing reflex.
We have higher brain centers that are obviously involved in sort of the processing of the urge to cough, the initiation of the cough, the intensity, whether you're gonna suppress the cough or even activate the cough. What we do know is that dysregulation of any of these pathways can lead to this concept of cough hypersensitivity. We're gonna shortcut a lot of the different big picture stories here to really get down to some of the essence. I think it's fair to say that cough hypersensitivity is really the underlying concept here for chronic cough. 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, you know, bouts of asthma or something like that, or just loss of lung tissue. The idea here on this whole chronic hypersensitization phenomena is that you have triggering stimuli that are more likely to produce a cough response than you had before. In fact, some things that may have never produced a cough response now can elicit that cough. The system is designed so that you have a direct pathway to the brain. We're not gonna take the time to go through spinal cord. The vagus nerve ends up being a very important part of the signaling pathway here.
You know, 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. In the central sensitization part of this story, we have things that are being amplified, whether it's, you know, excitatory centers that are being jazzed up or whether it's inhibitory centers that are being turned off. That kind of phenomena with the overall result of being hypersensitized, more likely to elicit this cough. That's sort of a little bit on the sort of the brief overview of the anatomy. When we talk about the pharmacology related to cough, there's lots of different things that you could be looking at. Of course, we're going to be talking about the opiates.
The opiates happen to be in the right place and sort of at the right time. When we talk about the opiate receptors, both in this peripheral and central nervous system schema, we're really talking about the opiates, primarily kappa and mu. When we look at the periphery part of it, we're really talking about, you know, phenomena like activation of opiate 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, you know, these opiate receptors, primarily kappa receptors being in the right place. When we're talking about, you know, this concept of sensitization, you know, these are clearly in the right areas of the brain that underlie or mediate this sensitization phenomena.
We're not just talking about cough, we'll be talking about pain and windup, and we'll be talking about itch and things like that. There is this concept of sensitization, this amplification process that is really occurring at both the peripheral and central nervous system level. The kappa receptors are really key here. When we think about nalbuphine and we think about our drug, let's think about it in concept of that. When we think of the opioid receptor system and we think about our kappa agonism, that's probably more related to what we're seeing here on the efficacy side. There's very good reason to believe that this is the phenomena related to the basic anatomy and pharmacology of what's going on here with sensitization.
As we think about opiates and we think about sort of the downside, the side effect side of opiates, we know that there's concerns about opiates. It's out there. When we think about this and we think about primarily the kappa and the mu 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 opiates. Not all opiates are the same. They have different levels of intrinsic activity. They can have agonist activity, they can have antagonist activity. We do wanna 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 kappa being important maybe for the cough response, but the mu antagonism here is really important for the parts that people get concerned about when you talk about opiates. The kappa 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. 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. It's been not controlled in the U.S. for a very, very long period of time, decades. I think that does reflect on its low abuse potential.
When we think about the classes of medications that are in the opiate class, we immediately think of drugs like fentanyl and morphine, hydromorphone, you know, which are full agonists. These are agonists 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 opiate antagonists. 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. You can give it to anybody who is suspected of having an overdose. It's that available. It reverses the effects.
When we look across this spectrum now of opiate activity, we have, you know, other drugs like butorphanol, which are more like partial agonists on mu, and they have some kappa agonist activity, but they're not quite as potent, let's say, as the drugs on the left, you know, the full mu agonist. We get to nalbuphine. Nalbuphine's down towards the naloxone. They actually have a chemical similarity here. What we're looking at is our kappa agonism, our mu antagonism, which really provides some unique perspectives on the drug and some mu 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, you know, that is a characteristic of this antagonistic class.
We also have data that says that nalbuphine, because of its mu antagonism, can reverse respiratory depression. That's been shown in people. It's been shown in animals. Very similarity there. We also think about opiate withdrawal. We know that naloxone and drugs like naltrexone can precipitate opiate withdrawal in people who are abusing opiates. We get the same thing with nalbuphine, right? We know that nalbuphine used in chronic users can precipitate withdrawal. When we think about this in terms of a spectrum, in terms of activity, not all opiates are the same. We have these full agonists here, full bore, high potency. We have the antagonist. We have kappa agonist activity in the nalbuphine, but on the safety side it behaves much more like a naloxone. I think that's just something to keep in mind. Not all opiates 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. We've seen that nalbuphine has not been scheduled in the U.S. for decades. Again, on the spectrum of scheduling and abuse potential, it's always been on that side of the story. A little bit of perspective on why opiates are important for cough, why nalbuphine is really important in the context of its efficacy in terms of kappa and its safety in terms of the mu antagonism. I said it was gonna be a little eclectic, so we're gonna switch a little bit now to our programs and really talk about our what's coming up and how things are shaping up.
Before we get there, I have to say, if there's anything you wanna take home today, it's gonna be our study names. There's been a lot of work that has gone on here. We can thank Katie and her team for really now our IPF program is gonna be OCEAN. We're gonna talk about OCEAN one and OCEAN two today. Our RCC is gonna be LAKE. You have to agree, these are beautiful logos here. Take them home. We'll give out pamphlets at some point. Let's talk about the actual framework of our trial. In the OCEAN program for IPF, we're gonna be running two trials. We've 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 one 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 one, followed by 3 weeks safety follow-up, where we're going to look at what happens when the subjects, the patients are off drug. We'll be looking at, you know, withdrawal symptoms and things like that are going to be very, very important from the FDA and from regulatory perspective. OCEAN-02, 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 gonna be the same as we talk about that throughout all the programs. When we think about this in terms of timeframe, as Jen mentioned, we'll be talking about our OCEAN one trial kicking off this quarter. We'll follow it up in 3Q with OCEAN two. We're looking at data readouts then, you know, in the second half of 2027 and in the first half of 2028. We're gonna talk about this in terms of halves. Don't read into where the diamonds are on the, on the plan. Those are not exact.
When we think about powering and how we're really prepared to go into our pivotal program, you know, for the primary efficacy endpoints for both OCEAN one and OCEAN-02, we're looking at greater than 9% power for both the primary efficacy and the key secondary endpoints. We are looking at the 54 milligram twice-a-day dosing. It's a 2-to-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 one, we'll probably be about 80-90 sites in the U.S., Canada, Spain, Poland, and U.K. 60%-70% of those sites will be in the U.S., or subjects enrolled will be in the U.S. In OCEAN-02, about 70-80 sites, you know, trimming back a little bit U.S., Canada, and U.K.
The primary efficacy endpoint is the same as what we've studied so far. It's what's driven us so far to this state where we're looking at the objective cough count, 24-hour cough count. The primary efficacy endpoint will be after 24 weeks of fixed dose in OCEAN one, 12 weeks of fixed dosing OCEAN two. When we look at the key secondary endpoints, here's our hierarchy. We're focusing on CS-NRS, which is cough severity, do some cuts of the efficacy data with cough monitor, cough frequency, patient-reported breathlessness, et cetera. 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 and what we're looking at for now.
This is our 1st parallel arm study looking in patients with refractory chronic cough. We have a screening period that will include a placebo run-in. We have 4 doses, or 3 active doses and placebo in here, where we are looking at 27 once a day, 27 BID, and 54 BID. The purpose of this trial, if you recall our RIVER data, we never established a minimally effective dose going at 27 BID, we actually are cutting the dose down to once a day dosing at 27. It is a parallel arm study. We are 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. As typical, you are 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 2027. What we are aiming for is the SSRE, sample size re-estimation to just gauge the size of the study that we went in with an N of 100. Make sure, like we did 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 N. 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. Our 4 doses, one-to-one randomization for 27 QD, BID, 54 BID, and placebo.
Based on the RIVER results and our data coming in from our IPF trials where effect size is 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. Our primary endpoints in terms of patient-reported outcome, looking at our essentials of cough frequency, cough severity. We're looking at quality of life related to cough, we are incorporating a urinary incontinence scale in here too because we know that that is one of 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 gonna be coming up.
When we look at the fundamentals of the design, it's very much like what you've seen. You know, 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. A 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. You know, the phase II-B portion of this is gonna 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, it will be a 4-week assessment here at fixed dose and then safety follow-up.
The phase III will be a little TBD at this point in time. We know what the FDA wants us to do for IPF. We will follow a lot. We'll pull all that into the program. Some of the numbers need to be determined here based on the outcome from this phase II-B trial. We're anticipating the same kind of thing with the safety, a lead-in period and 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.
Four weeks of fixed dosing for the phase II-B trial roughly ends of 100-120. 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. The scope of our program and the exact specifics with a 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 U.K. to do this phase II-B portion of it. The phase III will follow very similarly to what we did with IPF.
2-to-1 randomization just helps keep, you know, higher numbers of patients on drug, exactly what we're doing here for the IPF program. 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 gonna be a little bit eclectic here, but we have gone back and looked at a lot of our data. While, you know, some people ask us, "What are you doing?" Like, you know, "You gotta get phase III going." Like, there's a lot of analyses that we've done along the way to really help, you know, inform us on the kinds of things that we need to do here.
Wanted to touch base on this a little bit because adverse events, you know, we know this is an opiate class drug. There are known characteristics of adverse events. We're gonna talk about what they are and what we learned about them along the way. What's absolutely remarkable about this drug and its 50-plus year history is 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. When we look at what we saw in our RIVER trial for an RCC, in looking at the rank ordering of the common adverse events, I'm not talking about severity, but this is just in terms of occurrence.
You know, constipation, nausea, somnolence, 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 phase II-B study, nausea, vomiting, constipation, dizziness, headache, fatigue, somnolence. Rank ordering, they're almost identical. Again, across very different populations, we see a very what we would call well-behaved adverse event profile. 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.
When we look, you know, at our RIVER trial, the crossover study, we see that most of the adverse events that are occurring here that are GI or CNS in nature are really occurring with the first seven days of dosing. Keep in mind that over that first seven days, we're really looking at 27 BID. You can see things really fall off over the higher doses over longer time, which is really characterized here. 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 a strategy into our future trials. You're seeing this in our phase III program, where in LAKE and OCEAN, we 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 one 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 we start thinking about this in the commercial marketplace, you know, let's say you're gonna have these adverse events, they're gonna come on early. Just hang with it. You know, we can mitigate this to the extent we can. When they come on, they're transient. How often do they How long do they last? When you look at the most common adverse events that we have in our program, from constipation to headache to dizziness, you know, when we look at the medians here, the means, you know, again, first looks here, most of these, I wanna say about 75% of these adverse events that we see are mild in nature. That's very characteristic to what we see.
What we also see is that for the most part, some of these are lasting a couple days, like headache, you know, dizziness, you know, vomiting, even short term. When we look at, you know, some of the things that may last a little bit longer, maybe some of the constipation, some of the somnolence. On average, you know, medians or means, you know, these are still in a relatively short period of time when you start initiating these doses. 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, you know, try to mitigate some of these things for keeping patients engaged in our trials. I want to turn to the way that we measure cough.
The objective cough count is done with a device called 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, there were questions about whether or not there were issues with the cough counting. Merck was, they were first, and they had the bleeding edge of trying to get something introduced for cough. 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 used exactly the same system that we use, so it's this VitaloJAK. The program that GSK is running with the BELLUS drug is also using the same system. What's going on?
You know, basically, this system is designed to pick up cough sounds. It's got a, you know, 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. The issue comes with cough counting. This is a 24-hour cough count, and these are scored manually by people. There's a compression algorithm that is used, and I think this is the basis of some of the concerns they had with the initial Merck filing, is that, you know, you have to show that, you know, the way that you compress the data from a 24-hour recording 'cause it's manually scored down to something that's more manageable and something in the 3-4 hour time period, that it's a validated system and you're not losing things along the way.
All the algorithm is doing is taking out sounds where there's no sound. Taking out periods where there's no sound. The essence of this is you have a validated way for compressing the data down so that the counting can be done. I have to say that across all the programs and the FDA considers that manual counting with actual raters is the gold standard for doing this. We, like others, have had to then take a look at validating our cough counting. There was a validation study that we talked about in the past. This is really all about the compression algorithm that they use with this recording system. This all came out of the learnings and from the trials and errors of the Merck filing.
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. The nature of the validation study really was to look at two things. It was the agreement between the total cough 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. How tight is the relationship when one person's doing the counting versus somebody else doing the counting? 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. This is done on the data from the CORAL study, but it's again, not looking for drug effects. We're looking for the relationship between the compressed 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, you know, this agreement study, when you look at the plus or minus 10% here, represented by this purple band, you know, we're dab smack in the middle. 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 200-2,000 cough counts. This is one thing that shows that we have very high reliability in the compression algorithm that they use, and we'll be re-sending this in to 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. The other thing on the inter-rater reliability, there were 3 raters in this validation study. These are just showing you the relationship there.
With our purple being our bands of acceptance, our acceptance threshold, this is right, you know, zero and then a couple percentage points around the zero line over a range of cough counts between raters one and two and three, one and three. Very highly reliable cough counting. These are data that will support, you know, 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.
This is the first glimpse that says we have high accountability between compressed and uncompressed cough counts and high reliability in the raters that were there to do it. 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 end of phase II meetings. You always have a chemistry manufacturing control, a CMC meeting as well. We submitted a bunch of questions regarding our API about release specifications, you know, 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.
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. That's really the nature of this discussion at the end of phase II meeting for this CMC part. We talked about the acceptability of the excipient and 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 and a written response back from the FDA, so much so that we didn't even have to have the meeting.
We had a clinical meeting, but for the CMC and the phase II meeting, we definitely, you know, got the responses that we needed to move forward. We're feeling very comfortable about that as we look at our chemistry and the actual product that patients are gonna be taking, which we know is a very important part of the NDA process. Finally, I just wanted to touch on the fact that, you know, we had a lot of solid data that we generated in our program. We're having a very big presence at the ATS meeting coming up in a few weeks now. Some of the things that we just wanted to highlight to you is that we have a great presentation by Dr. Philip Molyneaux, who will be also who'll be describing what we have from our CORAL data.
We also have some interesting primary and sub-analyses that'll 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 bouts because people cough in bouts, and it's another very interesting parameter that everyone's interested in, especially the FDA. We started digging in on cough bouts. We'll be presenting some cough bout data from our CORAL study, but also be presenting some cough bout data from our RIVER study. There's some very interesting things that we found there. As we talked about previously, we have some very interesting findings on breathlessness from our CORAL study, and Dr. Donald 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 pirfenidone. We'll be presenting the data there. I'll be handling that poster where we found that there's really no effects in giving it mutual PK effects on pirfenidone or nintedanib with our drug. Of course, there's been some nice work on evaluating the sort of emotional and social well-being in patients, and this will be given by Srigurus, who will be really giving a poster on Monday. A lot of presence there, some new and interesting data that's gonna be presented there. Really looking forward. If you're down there, please stop by and see us. Turn it over to Jen.
Thank you. That 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 gonna introduce you to Dr. Toby Maher. If you ever saw his real CV, it's super impressive. Can you go back, 'cause I do wanna read his credentials. Oh, that's me, I guess. Toby Maher is a professor of medicine and director of an ILD clinic at the Keck School of Medicine of USC. You can see his division of pulmonary critical care and sleep medicine. We actually met him in the U.K. at the Royal Brompton just to add some personal flavor. Toby Maher's clinic was actually the first clinic to dose a cough patient for us in 2018. He's been a key advisor to Trevi along the way. He's reviewed our protocols.
He's gonna be in our OCEAN study, our big one. He went to the FDA with us. He's a very strong voice, not only in cough, but more importantly, in a lot of the IPF-ILD work that's going on. He presented all of BI's Cascade data. He is a big name. He's in the clinic today. We're super appreciative that we have him joining us. Hopefully, at the end, if Toby's got five minutes, we'll ask questions from the audience 'cause we will lose him. If you guys have things you wanna ask him, go ahead. 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. 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. Yeah, as you introduced me, thank you for the kind words. I first met Trevi, as you said, 8, 9 years ago now. It's been a journey. It's been quite exciting. It's been an important journey. I was in London, as you said, have now transitioned to the U.S., I've got experience of the trials and tribulations of trying to treat cough in two very different countries or two countries with very different approaches to symptom management and morphine-based or opiate-based treatments. That's been interesting.
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 3 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.
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, cough. There has been little that we've been able to do about it with our existing antifibrotic drugs. That remains as true now as it did a decade ago. 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 we're unlucky enough to get a respiratory tract infection and experience cough for ourselves. 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. 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 disgusted looks from fellow travelers as they sit there 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.
It's sort of one of the unspoken consequences of coughing, is that it will often exacerbate things like stress incontinence. It really is a very important symptom that can be incredibly debilitating for patients. Until now, there's really been nothing that we can do for it. You know, clinicians like to be inventive, so in clinical practice we use things like inhaled bronchodilators. We even use low doses of corticosteroids. We know that those drugs don't really work beyond having a placebo effect. There is a huge unmet need for effective therapies that moderate cough in patients with pulmonary fibrosis. I think as we look to the future, it is worth digging into United Therapeutics data with treprostinil. We know that inhaled 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. 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. We are shortly going to be in a situation where one of our approved drugs exacerbates one of the key underlying symptoms of the disease.
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 cough in these patients. I think cough is already an important issue, and it's going to become increasingly so when we have an effective antifibrotic and PH drug that causes cough as one of its side effects. 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 interstitial lung disease have made life difficult for ourselves by developing a nomenclature that is both repetitive and highly technical.
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 lung where gas exchange takes place. Interstitial lung diseases are characterized by either scarring or inflammation of the alveolar wall. Idiopathic pulmonary 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.
20 years ago, when we thought about developing anti-fibrotic 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. It was the disease in which it was most feasible to test potential anti-fibrotic drugs. It was also the most common of the many diseases that make up interstitial lung disease, it made sense to focus on idiopathic pulmonary fibrosis for those two reasons. 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. 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. 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 capsule term of progressive pulmonary fibrosis. 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.
When we take a step back and think about symptoms related to interstitial lung disease, these are really common across all of the disorders. Cough occurs with almost identical frequency across each of the different interstitial lung diseases. The vast majority of cough that we see in the different forms of interstitial lung disease has a very similar biology. Excepting that we don't fully understand the biology of IPF cough, 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. Those mechanisms that are important in IPF are exactly the same in other forms of fibrotic interstitial lung disease.
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. 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. 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.
Certainly as someone seeing these patients in clinic, the need for a treatment for cough is just as great in this group of patients. Just to finally give an idea of the importance of this group of patients, about a third of the people I see in my clinical practice will have Idiopathic Pulmonary Fibrosis. The other two-thirds will have other forms of pulmonary fibrosis and Interstitial Lung Disease. For me, it's very important that Trevi has these plans to extend into ILD, because whilst having a drug for cough in IPF is going to be important, I'm still going to be left with two-thirds of my patients for whom I need a treatment.
The plan to follow on very quickly with an approval study in interstitial 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. I think I'll stop there and, if we've got time for questions, happy to answer them.
Oh, wow. A lot of hands went up, Toby, but thank you so much. Every time I listen to you, I learn things. Do we have some microphones here? Annabel, I'm gonna start with you. Oh, they're coming. Hold on.
Hi. 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've progressed more rapidly and had greater cough during that time period?
Yeah. I think that's an important clarification. I think the rate of progression is important if you're developing an anti-fibrotic drug. If you're developing an anti-fibrotic 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, Philip Molyneaux, 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. Patients with fibrotic lung disease are either coughers 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. When you look at cough and pulmonary fibrosis, if you just look at cough counts. 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. The impact of cough 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.
The impact on quality of life does change over time, but the severity in terms of count doesn't. I think, again, it's a long-winded way of saying actually that 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 that patients have cough as a symptom, and if they do, then you're gonna have a big enough delta between active treatment and placebo to be able to show an effect of therapy.
Go ahead, Kaveri.
Thank you. Hi, 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 and connected to ILD and IPF. How much cough and the intensity of it actually plays a role in lung deterioration by the mechanical damage which can obviously induce cough and provide a positive feedback loop or the inflammation, reinflammation you said. Do you think addressing that with something like Haduvio, given its biology, could slow the lung deterioration process in long term?
That's a really interesting question, we don't fully know the answer. Again, interestingly, going back to the study that we did with our patients in London, we looked at about 600 patients. We had 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. We used visual analog scale, which is a pretty good way of determining cough severity in patients. We did see that there was a relationship between cough severity and subsequent survival that was independent of disease severity measured by things like forced vital capacity.
That is tentative data suggesting that cough in itself is a determinant of mortality. There's one other study published in the literature that showed something similar with this relationship between cough and survival. 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. 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? It is plausible that an effective cough treatment could improve survival.
Toby, do you have 5 more minutes for us? I know it's 8:00 A.M. Okay.
Yeah, I can give you five minutes, Laura.
There's a lot of interest in hearing from you. Alexa, Josh, do either of you have a question or no? We can keep it moving. Okay. I know Lee, Lynn, and Jude had, the mic can go back to them. Ryan, I'll come back to you. I'm sorry. I didn't see you. Go ahead, Roanna.
Hi, 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 that treatment paradigm? 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?
Yeah, and I. A good question. I think, I'll apologize, I'm still trying to get to terms with pronouncing Haduvio, so I'll stick with nalbuphine because I know I can say that without tripping myself up. I think you know, as I would see it's something that sits separately to the antifibrotic drugs. You know, my patients are gonna 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. 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.
I can foresee that we will use Haduvio in parallel with anti-fibrotic drugs for that proportion of patients in whom coughing is contributing to their loss of quality of life. As you say, TYVASO is sort of an added wild card because that in itself triggers the cough. You know, we've been using it for two or three years now as a treatment for pulmonary hypertension related to IPF. We do have experience in this patient group, and really the major reason for discontinuation is the coughing. That is despite the fact that patients often see symptomatic improvement when you treat their pulmonary hypertension with TYVASO.
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, it is something that we would want our patients to be on. I'm, you know, I'm not, you know, 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 gonna do one more question. I'll get to some of the others of you in our next session. Leland, go ahead.
Thanks for the time. Thank you for the discussion, Dr. Moore. This is Leland Gershell from Oppenheimer. Just a quick question for you in terms of market opportunity. As investors, we think about, you know, how Haduvio out there once it's presumably approved. It sounds like, you know, same frequency of cough in non-IPF ILD versus IPF in about two-thirds of the patients usually have non-IPF ILD. In addition to that, being that non-IPF ILD presumably has lower mortality, should we think about the use of Haduvio be longer in each patient? Would the per patient use of Haduvio be for more years than it would be for IPF, given the relatively short lifespan those patients have once they're diagnosed? Thank you.
Potentially, yes. I mean, if you're trying to model all these things, there's probably 3 buckets I would divide my patients into. There's the IPF bucket, which is roughly a third. There's the autoimmune related ILDs, which are roughly a third, and they're definitely the ones where there is a much better prognosis. Those patients are, you know, can expect to live for a decade or more despite their interstitial lung disease. The middle third is the sort of mishmash of disorders that includes things like hypersensitivity pneumonitis, some of the pneumoconioses, so things like asbestosis, albeit that's getting rarer these days. The various other things such as idiopathic NSIP and unclassifiable ILD that you will hear other people talk about. That middle third probably has an outcome that better approximates IPF.
If we're saying 3-4 years for IPF, we're probably saying 4-5 years for that middle bucket. You've got IPF is the worst. You've got the middle bucket that's almost as bad, and then you've got the autoimmune ILDs, which do have a distinctly better prognosis. Yes, for those patients, they will have a longer duration of symptoms like cough as well.
Okay. Toby, we're gonna let you go. Thanks so much. We really appreciate you dialing in, and we'll send you off to your patients.
Perfect. Good to see everyone. Have a good rest of the meeting.
Thank you. Okay, we've got another equally as special gift in having Peter Dicpinigaitis join us. Peter is a professor of medicine at Albert Einstein College of Medicine. He's 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-in-chief of LUNG, and he also runs the American Cough Conference every other year. 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." I actually had him present to our board, because of Peter's sort of passion around getting options for his clients, we are now sort of moving down that path. We're very happy to have him join me for our fireside chat, and he made sure there was a fireplace and I wasn't lying. He's also gonna be here for lunch. We'll take a few questions and, but he will also be here through lunch. Come on up, Peter. Those are big shoes to fill after Toby, huh? I have confidence.
I can't match Toby's beautiful Southern California accent.
Yeah, right. Peter, why don't we start off with you just giving a little background on yourself. I know I read from the slide, maybe you can put it in your own words.
As you mentioned, I spend, I'm a pulmonary critical care physician. I'm a professor of medicine up in the Bronx at Montefiore Einstein. 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 cough in 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 started my cough center in 2003, and actually I'm up to over 2,800 patients that I've personally evaluated with chronic cough. It's a fascinating group. It's a tough group.
You know, I'm happy to say that 15, 20 years ago, there were no pipeline cough drugs, now we have maybe six, seven or eight that I can think of off the top of my head. 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 cough reflex. It's been really gratifying seeing us go from zero to a bunch of phase II and now phase III trials. Really excited to have something in my hands soon that I can use.
Great. I'm gonna ask a couple questions, but then I'd love to bring the audience in. Think of what you would like to ask Peter. Peter, I know it's been a journey, even in sort of the five or six years we've been in it, of how you clearly define these patients. 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. Maybe you can talk about that 'cause you've been on the forefront, I think, of trying to get this defined and the right patients.
Yeah. Talking about anything, it's important to define what it is we're talking about. Chronic cough 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. Refractory chronic cough is a specific thing, and that means it's a chronic cough that has not responded to appropriate treatment for the 3 main baskets of things that cause chronic cough. What we now call, number 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 eosinophilic bronchitis. Number 3 is GERD, acid reflux.
If the 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, RCC. You know, we're the small group of us in cough that do a lot of education to our colleagues at, you know, at grand rounds and at conferences, we, you know, we really stress these definitions 'cause most of the drugs in the pipeline now are gonna be labeled for RCC. We as physicians are gonna need to know when is it appropriate to prescribe these drugs that hopefully we'll have in the next 2 or 3 years.
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 in IPF or ILD is so much worse than RCC, that RCC is sort of less bothersome. I would love your perspective on that because I don't think that's necessarily true, but maybe you could share. I mean, you see these patients.
Yeah, you know, it's bad enough that, you know, the lay community doesn't appreciate what RCC can do to a patient. You know, it's not an annoyance, it's not a pain in the butt thing. It's a life-destroying entity. When I'm at my cough center, very common for me to see a patient who has been coughing every single day for 5, 10, 20 years, haven't been to a restaurant, theater, to church for 10 or 20 years for fear that one of their cough bouts is gonna 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? this is an annoyance that these pe-folks are clinically depressed. As Toby said, they become shut-ins. They're afraid to go out in public for fear of one of their cough paroxysms. that was before COVID.
You can imagine what's going on now. It's a problem. 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.
These are things that really aren't appreciated 'cause, you know, these folks become socially isolated, so they're not really out there. Toby mentioned urinary incontinence. 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.
Wow.
62%. Thank God, cough syncope, fainting from cough is much more rare. I do have a handful of patients that have such frequent cough syncope that they have essentially become shut-ins because any time they have a bout of coughing, they can just faint.
You don't wanna be waiting for the subway or driving when that happens. You know, we always try to teach our colleagues really how debilitating RCC can be. It's not, you know, just a cough, you know, don't worry about it.
Yeah, that's helpful. I always mention this, but in our RIVER study, we had one patient who coughed 2,500 times a day. I mean, it's really stunning how much they cough. Any questions from the audience? I can keep. Oh, yeah, please, Judah. We'll get you a microphone.
Thanks. Judah, Morgan Stanley. Just curious on kinda, you know, standard of care here. You know, how would you characterize it? You know, how quickly do patients move through whatever you're able to prescribe for them? There's 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. Thanks.
Okay. The first part, I think 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 Montefiore or if they live in the neighborhood. I'll see the cougher for 4 months, but very commonly 10, 20, 30 years. I'm 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, ENT, GI. 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.
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 tests that they don't need, et cetera. Very, very variable, really depending how lucky you are to be able to get into a situation where you're seen by doctors that are comfortable with treating cough. It could be anywhere from a couple of months to decades. I think the second part of your question, I guess, was,
Standard of care, can we talk about now?
Yeah. really the standard of care that unfortunately we still have to teach and drum into our docs is that, you know, when a doctor first meets a patient with chronic cough, their job isn't to say, "Well, here's a gefapixant that I got from Europe," or, "Here's 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 cough 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.
I have the diagnosis of RCC. Let's say we've actually made the correct diagnosis of RCC. In the United States, we have now obviously zero options for treating RCC. We have no Forget ours, we don't even have a drug for chronic cough. Right. The last. Does anyone know when was the last cough drug approved by FDA? This is the audience participation part of the talk. Last cough drug by FDA. Now you have one? Come on, you guys are cough folks. Last cough drug by FDA. 1958. Extra credit. What was it? benzonatate. TESSALON Perles. These nice little yellow gel-through caps. Very aesthetic-looking capsule. Very pretty. Those were approved for. dextromethorphan was 1954, I think. These were for acute, subacute cough. 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 parentheses in the United States because we now have gefapixant in Japan, and in Europe. Right now we have nothing. What do we have? When we get to the diagnosis of RCC, the therapeutic landscape in the United States is, number one, classic mu-opioids, morphine, hydrocodone, codeine. Not good options for something that may be chronic therapy. What we tend to go with is the so-called neuromodulators, amitriptyline, which is an old tricyclic antidepressant, 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.
The bigger problem is the patient has to tolerate the dose of the drug that makes their cough better. Especially with gabapentin, I have had tremendous difficulty with intolerable sedation from gabapentin. There's one randomized controlled trial showing that 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. You know, so that's why our options are very poor. We've also learned that the speech-language pathologist can be very helpful as part of the chronic cough teaching team, but there's very few of those folks around.
I might anticipate a future question by saying that, you know, when people look at some of the nalbuphine work, they said, "Hmm, 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." you know, just to give a little perspective in terms of what, you know, what we have now.
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. How big a hurdle is that gonna be for doctors, for patients?
Right. That was part three of your question.
Yeah.
Okay. Thank you.
I'm remembering, dude. I got you.
Yeah. anytime there's any new drug, right, there's a lot of teaching involved, right?
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 was a terrible disease that killed young women. 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 cough and what is RCC. Also we're gonna need to remind our physician colleagues about what they learned in second-year medical school in pharmacology class-
where there are different opioid receptors, and the ones we're most familiar with are the drugs that are mu opioid agonists, like morphine, hydromorphone, codeine, et cetera. Those are the ones that carry all the bad baggage and about which we are fearful. We're gonna need to then teach that nalbuphine seems to have its antitussive effect through the kappa receptor agonism, and interestingly, it's a mu antagonist. That's gonna be very important teaching for our colleagues to say, "Oh, well, yeah, I mean, it's an opioid because that's a general term, but mu and kappa have very different, you know, different meanings and different, you know, pharmacological issues." The teaching is gonna be necessary.
The thing is, you know, 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. 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 with gabapentin or even sometimes amitriptyline. Yeah.
Great. Ryan. You're getting a workout, Katie.
Thanks for the question. Curious on what, in your experience, with your patients, time to diagnosis looks like. Speaking of some of the antitussives that are out there, TESSALON Perles and gabapentin, are there certain patient subgroups where those work better than in others?
Yeah. you know, the first question is literally unanswerable because as I said, if I'll see someone who's been coughing 2 or 3 months, and other times I will literally see people that have been coughing for 20, 25 years. it really depends on how fortunate or not fortunate they were to have gone through an appropriate workup of chronic cough before coming to see me. you know, by the time folks have seen me, they've tried everything. you know, benzonatate really is like a coin flip. It works for 50% of the time in someone who has, what we call an acute or subacute cough that is always due to a respiratory tract infection. as I said, it's not approved for chronic cough.
They've tried the dextromethorphan, benzonatate, oftentimes short courses of codeine given by their desperate primary care doc. There's nothing reliably that works. As I said, with amitriptyline and gabapentin, the two so-called neuromodulators that we use, they're off-label, but we have nothing for chronic cough in the States. My experience has been very poor, both in terms of their efficacy and tolerability.
Kaveri.
Thanks. Kaveri Pohlman from Clear Street. Just to follow up on the standard care options. 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? Any comorbidities in the patient for which you would avoid giving this drug to? Yeah, just kinda like starting with that.
Yeah. Remember, when you have zero, anything other than zero is good. The day the first drug for RCC is approved, every single patient with RCC would be a candidate for that drug, whether it's camlipixant or nalbuphine. Why? Because we have nothing approved, so the first RCC drug will be appropriate for everyone. With nalbuphine, I guess I would make sure to see what other drugs the folks may be on, you know, that may be potentially sedating. That would be something I would keep an eye out for.
All right. Maybe quick one on, you know, 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? Thank you.
Yeah. Cough is interesting, right? 'Cause cough has both a measurable objective component and a subjective component, right? If you're doing a blood pressure study, well, your BP is either 122 or 82 or it's not. With cough, you know, we have. The FDA wants us to measure cough. But regardless of whether the cough count comes down, you really want your patient to say, "You know, I feel better." There's both a subjective and objective component. To get the drug approved, we'll need to give FDA both objective and subjective. But when we are dealing with a patient and, you know, 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? It's really as simple as that.
Annabel, 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, P2X3 that come into the market earlier. Haduvio has shown activity across the spectrum of severities, and P2X3s were primarily severe. When you see a patient, how do you determine whether they're severe or moderate, whether 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.
Well, if they're in my office, they're severe, but that's 'cause I run a central cough center where I see these folks. I think the most likely way things might play out, for example, is let's say, camlipixant gets approved first, which seems, you know, perhaps likely. We know a lot from gefapixant and camli that there's at least a 30% non-responder rate with the P2X3 drugs. That's true for a lot of drugs, right? I don't know of any drugs that have a 100% responder rate. There's a large non-responder rate with the P2X3s. Even the responders, they don't go from a bunch of coughs to zero. They go from a bunch of coughs to a lower number of coughs.
The P2X3s are not lifestyle drugs. Let's say if nalbuphine is the second drug approved, we will already know what camlipixant can or can't do. And again, you know, these are not lifestyle drugs. I think camlipixant might not be as potent as gefapixant, but we'll see. There'll be a lot of non-responders and partial responders. Any second drug that becomes available, it would be, you know, appropriate to see if that drug is better, either as an add-on or instead of. That brings up a more important point, and that is peripheral versus central activity, right? There was a nice figure, I think Jim showed, where like in the lung, there's all kinds of receptors, right?
There's P2X3, there's TRPA1, TRPV4, TRPM8, voltage-gated sodium channels. 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 NaV1.7 voltage-gated mechanism. 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. 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, TRPV1, et cetera.
that's why to me it wasn't surprising that the nalbuphine data were not only was the cough frequency reduced to a great extent than any other drug we've seen, but high and low coughers 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 asked the question, I said, I would be asked, "Well, what's the ideal cough drug?" I would say, "Well, a centrally 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 or receptor happens to get stimulated to start the afferent mechanism of cough.
great minds think alike 'cause Annabel, that was my question. Josh, we're out of time, but I'm gonna give you one because I wanna bring you in. go ahead.
Thanks, so much. Josh Schimmer from Cantor. Do you need both the kappa agonist and the mu antagonist effect to impact the cough? If not, a question then for Trevi, would you have any lifecycle extension plans to isolate the active component? Thanks.
Not being a pharmacologist, that's a little above my pay grade. Certainly from the data we've seen, you have to assume that the kappa agonism is responsible for some, if not most of the antitussive effects. Whether there's any mu involvement, you know, 'cause there's an agonist/antagonist situation going on there. Again, not being a pharmacologist, I don't think I can do justice to the question.
Yeah. I think we believe, Josh, it is due to the kappa. 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. It's a good question and more that we'll share over time as we move forward. Thank you for the question. With that, I'm gonna wrap up this section so we can keep moving. Peter, thanks so much. 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 gonna turn it over to Phil to take you through our commercial work that we've been doing.
Thank you, Jennifer, and good morning, everybody. 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. 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. When you look at this, they have no options. It's a persistent cough that requires a chronic therapy.
We did, you know, we look at the commercial strategy through that patient lens. There's a couple 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. 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.
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. We did a piece of research in partnership with the Pulmonary Fibrosis Foundation in the U.S. These are approximately 200 patients from their community registry. What you see here is the striking burden of chronic cough among these patients. 78% of them, once they begin to cough for more than 30 seconds. These are these cough bouts that Toby and Peter talk about. This is what impacts these patients and brings them a lot of times to their knees. 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.
Two-thirds of these patients are not satisfied with their current or prior therapies, and that's consistent across the work in which we've done. These are a patient population, and this is among ILD patients. As Toby talked about, they're very similar between IPF and non-IPF ILD, but it's consistent across the ILD population. From that same piece of research, just echoing some thoughts that Toby had, these patients when they self-assess their cough severity from the date of diagnosis to where they are today after a couple of years, they are either the same or worse. Cough doesn't resolve itself in these patient populations. 76% of patients with chronic cough will have had their chronic cough for greater than two years. 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, and 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 it increases specialist visits. 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 healthcare resource utilization. This is a slide I'm gonna 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.
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. The antifibrotics, most importantly, do not affect chronic cough. 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 time. Patients are also frustrated within that same feedback loop. Patients haven't removed themselves from 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 effective therapy. 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. 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 gonna be early in the treatment algorithm across all of these conditions. One of the cores to this is our specialty pricing because of the small patient population which we'll launch with IPF and take into these additional populations. this is a scalable growth model that we have without incremental commercial complexity. 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 is the only therapy left in development, in 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. 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. 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.
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 eights. 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. You see some of the quotes here, and I think it's some impactful language, which I'll just read. There's a very high unmet need. Chronic cough is often a major driver of clinic visits and contributes significantly to patient dissatisfaction, making effective treatment options critically important. It's a major driver of clinic visits. These are our target pulmonologists, and they're ready for a therapy within this space. This is the category before we show them our product.
when we translate and show them our target product profile, we ask them on three dimensions. The x-axis is efficacy, the y-axis 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. This leads directly into intent of how do physicians intend to use this and what patients they intend to use this in. 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." They're already positioning this as early treatment and not as a last line resort. It shows up in how they intend to use it in their IPF population. This is the same 90 physicians about IPF. They wanna use it as combination therapy with those anti-fibrotics. 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. We heard in other pieces of research, some physicians would even look to initiate Haduvio before an anti-fibrotic because the patient's gonna feel better, and they know they're gonna feel worse on an anti-fibrotic. They can get a quick win with these patients.
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. There's confidence. It builds our confidence behind the rapid uptake. When we look at that uptake curve, that access builds quickly. We expect prescribing to begin rather rapidly and to mature within about two years. That is expected because of the access landscape and the lack of available treatment options here. It's consistent with other special respiratory launch items in areas of high unmet need. That's a lot of our physician work that we've dug into over the last year. We're now transitioning over to payers. We've talked to 15 payers in the U.S. that cover most of covered lives across books of business.
What's striking here is the similarities that we receive 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. 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. When you look at what payers feel as important measures to themselves, there's really three things, the clean indication, credible and reliable efficacy and durability, as well as predictable utilization. Haduvio is able to deliver on all three of those metrics for payers. That translates into our pricing corridors of where do we anticipate pricing to price IPF at launch.
We tested $75,000-$125,000. Across this entire range, you don't see significant difference. Pricing is rather inelastic, and that's because they will use utilization management in order to restrict us to label, enable prior authorizations, and require step-throughs. This is the same framework that anti-fibrotics are on today. Specialty tier, step-through therapy, first-line though, and patients get covered. We expect to be right where anti-fibrotics are in an established framework with no new access model. This is very familiar to payers. That's the IPF story. Now it's how do we efficiently expand from IPF into this non-IPF ILD category? You heard from Toby earlier, physicians see these categories as almost one and the same. There's been a lumping and a splitting of ILDs over time.
Feel like this, 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. 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. 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 of life impact as to IPF. 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. Physician setting, the pulmonary fibrosis care centers in the United States are ILD care centers.
They're not IPF care centers. Where we're gonna be already in IPF will already have covered ILD. 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. 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.
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. They've added, I think, 10 of these centers over the last year or so, which is great to see. That enables us to efficiently target them with a field force of 50 to 75 reps at launch. This is where our operating leverage comes from. 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.
I think Toby did a really nice job of just reinforcing the patient population of how much of this is IPF 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 one-third, two-thirds. 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 expand it 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 there's strong precedent from the anti-fibrotic space. Anti-fibrotics, as they launch or as they expand, they maintain the same list price from IPF to that broader category of PPF.
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 this to occur. 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. It's an even larger opportunity by doing so. When we look at RCC programs, the competitive landscape is similar. Multiple failures because of that peripheral nature of that disease, but the central component matters.
Haduvio is well-positioned within this space, perfect for those who have failed other therapies that may be off-label. We go back to that piece of research of I think Jennifer asked the question, are they seen as any less severe? These patients are seen 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. The commercial approach translates well with a primary call point as pulmonologists. 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 where 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. 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? 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? 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.
What we'll look at is this subpopulation, and I'll get into the TAMs in a second. We're not looking at a new framework here. We're looking at an extension, but de-risk the payer for a manageable, predictable size of this market. 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. Factors of our specialty pricing, which we'll launch and take into these indications, as well as the expected gross to net. Jennifer already mentioned the large TAMs, $5 billion+ in IPF, $7 billion+ in non-IPF ILD, and $20 billion+ in treatment-resistant RCC. Question is, then what can we achieve at Haduvio?
When we look at IPF, we can achieve a large market share being the only first-in-class, best-in-class therapy, 25%-35% share. Similarly in non-IPF ILD. We've purposely took a modest 3%-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. 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 pulmonologists as a clear call target. A clear line of sight to value creation. With that, I'll turn it over to Dave.
Well, thanks, Farrell. You know I like my numbers in the billions. You know, it's very exciting. Good morning. Great to see so many familiar faces in the audience today, and thanks to people listening in on the webcast. You know, I've been subject to a fair amount of ribbing the last couple weeks from my colleagues at Team Trevi, because I was given the burden of actually presenting and preparing one slide today. I better not screw this up. Moving on here. Really wanna focus just 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 $162 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. A very successful follow-on offering there. If you couple that with the $162 million, the $72 million we reported a couple days ago at the end of 3/31, we extended our cash runway into 2030. Importantly, that drives a lot of clinical value for Trevi. 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 in our lead indication. In addition, it buys us the 2b and, potentially a phase III in the non-IPF ILD indication, and it'll buy us that top-line data.
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. With that, I'll stop and turn it over to Jennifer.
You nailed that one slide.
Yeah.
Jim's been ribbing him 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. IP. I wanted to spend a minute here. We've been investing a lot of time and resources into protecting this. I personally have become very convinced this drug works. I think Farrell did a really good job of showing you this is a big market opportunity. I think our ability to protect this and extend the patent life around this is really key in driving tremendous shareholder value. 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 patents. 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. 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.
As you can see from this slide, we've got our broad foundational patents that have either been issued or in late stage. 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. I have a lot of confidence that these are well protected through 2039. Now Tom's mission is to essentially take that 2039 benchmark and extend that runway. Fortunately, because we now have clear line of sight around our label, we're able to now start building around these label claims.
Dosing in hepatic impaired patients, the actual titration schedule Jim took you through, lot of phase I work going on, formulation work going on. Anything filed, for instance, this year in 2026, those are 20-year patents if they get issued. That takes that 2039 benchmark to 2046. What I can assure you as investors and analysts in the company, this is a very high priority for Trevi, and we have three years to continue to invest here until this drug gets launched, and we will continue to build out this patent estate. Last slide. You've heard all this today, but there's a lot of data coming around. We mentioned that we're gonna be starting OCEAN one 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 2b and ILD kinda 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 upsize? You can sort of read between the lines on what we're where we're heading with that. Three key trial readouts in the second half of 2027.
Our second OCEAN study, the 12-week study Jim took you through, we'll get the first look at the phase IIb in ILD, that'll be telling about what that phase III trial looks like. The full readout from our RCC trial in the second half of 2027. Our larger OCEAN 1 trial will read out the first half of 2028. Jim has got his team focused on roughly six months later, an FDA submission. We would look to, if you roll all these timelines forward, a launch in late 2029. We're pretty excited about it. I joke, Tom will appreciate this, we may live to see this drug approved, Tom. There were days in my life I actually doubted that, but it's been-
Threw the coin in the fountain.
Yes, when I threw the coin in the Trevi Fountain. Anyway, with that, I know we're right about at noon. We're gonna 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. I'd like to invite the speakers up to the stage and, please raise your hand if you have any questions you wanna ask. 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.
Did you pay him for that?
Do you see a path to a broad cough label, maybe carving out who have some kind of a reversible component to it? Can we just kind of keep running the same study with the same results over and over?
Jim, I'm gonna give an answer because we talked about this early on, but I want you to answer. Jim has been 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, you know, an IPF patient is quite different than an RCC patient, even though chronic cough sort of underlies it. Tom and I heard in the early days with the FDA, that was not something they were particularly interested in. Now, things evolve over time. Jim, I'd love you to give your views on that as well.
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, you know, they'd rather be more specific than go broad on an indication like this. I dang it, you know, putting the trial in the context of specific populations like IPF, you know, it allows the division to really look at it in relationship to the specific risk-benefit as it relates to that. As you can imagine, you know, RCC population versus an IPF population from the FDA perspective might have very different risk kinds of benefits. 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. 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 cough, and we heard like 200 different etiologies of known IPFs.
Yeah. I think, but I think that that's where the key is, right? I mean, there-
That's right.
Clearly are more specific populations that we'll get to first.
Ryan, you can hand it back to Judah when you're done.
Thanks. Curious what the Trevi team has seen so far on urinary incontinence with Haduvio so far. For Dr. Dicpinigaitis, I guess, how are you thinking about breathlessness in the context of RCC, how important that is?
Jim, why don't you comment on-
I'd just say that briefly, I mean, we're gonna 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?
As far as the breathlessness, the RCC group is interesting. RCC patients, the classic RCC patient is a woman in her fifties or sixties. Chronic cough centers, like mine, two-thirds of the patients are women. Women have a more sensitive cough reflex. Across the board, it's a female predominant thing in RCC. These folks oftentimes are otherwise fairly healthy. They typically have normal lungs, not so much in the way of medical issues, it's just the RCC has destroyed their lives. Breathlessness tends not to be a problem except when they're in one of their prolonged coughing bouts, where obviously then you're short of breath. Very different than the IPF population, which is mainly men, in their seventies who have, you know, smoked for decades. They're an older, more frail group.
The RCC group is typically a healthier group for whom RCC really is the main issue.
Judah, go ahead and have that back.
thanks, 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 Simon, on commercial opportunity. you know, we hear estimates out there that, you know, non-IPF chronic cough could be significantly higher, you know, in terms of epidemiology than what we think right now. I guess, you know, is there upside to the addressable market in non-IPF ILDs and kind of could incidence in that indication be significantly greater than what we know it is today? then in a world where Haduvio is approved in that indication, could you see that encouraging increased diagnosis?
it's a great question, Judah.
The way we arrived at our non-IPF ILD population is we did a targeted literature re-review of the specifics, not all 200, but call it the top 100 of those individual disease states and tried to characterize what proportion had a dry chronic cough as part of their presentation. That's how we arrived at the, let's call it 228,000 in non-IPF ILD. I think as we get into it. 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. Yeah, Brandon, you haven't gotten into this, so I'll hand it back on. Thanks, Kelly.
Brandon Price, H.C. Wainwright. Maybe just following on that. In the RCC population, how do you think physicians are gonna view camlipixant partial responders if Haduvio is approved as well? Are you gonna view this as a treatment success and keep the patient on therapy, or could you move them to Haduvio?
RCC.
You know, if a patient has a terrible cough and they have a 20% improvement with, let's say, camlipixant, that's not gonna be good enough. The question is, 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 camlipixant. I would exchange it for camlipixant. You know, you can use both together. The proof is gonna be once both drugs are out there. Theoretically, a centrally acting drug is gonna trump the peripheral. I would exchange rather than add on.
Yes. We hand it behind you, Brandon. She didn't, she hasn't gotten a chance. Thank you.
Hi. Thank you so much for the presentation. My name is Avni. I'm asking on behalf of Debanjana from Jones Trading. Are there any specific commercial lessons that you're drawing from Insmed's BRINSUPRI launch around pricing strategy, payer engagement, patient physician education, and how that relates to Haduvio?
Short answer, yes. I think Brinsupri had a phenomenal launch. I think Verona, you know, 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. We have and will continue to dig into that launch so that we are set up for success.
Thank you.
Okay, maybe hand it back up. We'll get over here to Roanna. I'll get you two, and then we'll wrap it up.
Thank you. Hi, I'm Roanna Ruiz from Leerink Partners. I was thinking about the non-IPF ILD study that you're gonna gear up and anything special you need to think about in terms of inclusion, exclusion criteria, finding the right patients, knowing that ILDs can be a basket of many different types of patient groups.
It's a great question, and we actually had an incredible advisory board on this a number of months ago, actually last year.
Because it is a complex population. 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, you know, the defining characteristics, and Toby said this, is that they have a certain amount of lung disease, and they have cough. If we ignore the basic population comorbidities that can occur with these underlying conditions, you know, people with RA or Sjögren's, et cetera, you know, it really comes down to how much fibrosis do they have? How much cough do they have? We're gonna take a very unified but simple approach to that study, and we're gonna be identifying patients that have, regardless of the comorbidities and maybe con meds that we have to sort of figure out some details about.
It's gonna be people who have a certain amount of fibrosis in the ILD category and a certain amount of cough. I think it keeps it sort of across the board, it's gonna be focused on the essential elements.
Annabel.
Thanks. 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? One more question.
when we look at the difference in total daily dose between IPF and ILD, which I think setting out there, 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. The one thing we will not do is sacrifice pricing or cannibalization in our IPF or ILD market.
Okay. the second question, when you were 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 where do you expect that step edit to be?
off-label therapy.
Off-label.
What they're standard of care.
How do they establish that?
How they establish standard of care versus what they're using today, so Tessalon Perles, neuromodulators, pretty much what they're using today in that environment.
Thank you.
Okay. Bring us home, Kaveri. Last question.
Thank you. Kaveri from Clear Street, and thanks for hosting this insightful event. It was very helpful. One question perhaps maybe for Jim. You know, there are some publications suggesting that, targeting P two X three impacts the expression of opioid receptors. I was just wondering if, you know, you can provide any insight on how and if a P two X three, antagonist could impact Haduvio's efficacy, if there's any biomarker data or any literature that can-
Thank God you got that question.
be clear on that.
Well, yeah. That's a tough last question. I don't
I have another one after that.
I don't have any direct evidence on that. I think, you know, as we look at this, you know, and whether or not there's gonna be combination therapy, as Peter says, I mean, I think there's gonna be, you know, the likelihood that in the RCC population that it may be an 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, you know, 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 this amplification processing where maybe we have the opportunity to damp it down.
I don't have any direct evidence that a P2X3 activity, which we know there are receptors in the brain, those drugs don't work there. You know, I don't know if we have any evidence that would suggest that one would affect the other.
Got it. Maybe the second one is very simple. There were some previous discussions to study, like the QD potential for Haduvio in phase II, the RCC trial, beyond the titration period, obviously. I was wondering if that's still of interest, that's something you can probably do in the future.
For RCC and for phase II
We have the QD dosing for 27. That'll 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. If we start seeing that, we're gonna go back and explore the really low end of this dose range. Our colleague Steve's in the room, but he's out working on much lower dose formulations, which could open up a whole another opportunity to really go at the market separately. We'll just go where the data takes us.
Yeah. I think just one addition to that is that when we think about it in terms of, you know, pharmacology and metabolism, our half-life is about eight or nine hours. It actually could support a once a day dosing, just to throw sort of a critical factor back in there. I think there's a reason to believe that once a day, regardless of sensitivity in RCC patients, et cetera. From a pharmacokinetic perspective, I think our half-life is sufficient to support once a day if it's gonna work.
Very helpful. Thank you.
Good. We'll wrap it up for the people that have to go. We're all gonna be around till one. If the team could migrate over towards lunch. Couple other logistical things. We did bring Trevi Owala water bottles. We'd love you guys to be advertisers for us. We just really appreciate everybody that showed up in person. Thank you.