Okay, great. So hi everyone, my name is Nicole Martucci. I'm from the biotech research at TD Cowen, and it's my pleasure to introduce our next feature presentation from Trevi Therapeutics. With us today we have Jennifer Good, President and CEO of the company. For the audience, we will have the opportunity to ask any questions at the end of the presentation, and with that I'll let you take it away.
Thank you, Nicole, and thanks to Cowen for having us. You guys have certainly kept Lisa and I busy today. I'm joined by our CFO, Lisa Delfini, as well. So I'm happy to share the Trevi story with you. 2024 is a fun year, lots of data readouts coming, so I'll take you through that. We have been on a journey over the last 10 years. I'm one of the two co-founders of the company and have been through sort of pruritus and cough and ended up based on the data from both, which were both positive trials. The data was really compelling in cough, so we've decided as a small company we're going to focus in on cough. So we have two lead indications. One's chronic cough and IPF, the other is refractory chronic cough.
We also are doing a couple of supporting clinical studies this year, some respiratory physiology work, and also a human abuse potential study, which we'll talk a little bit about. Sort of in a nutshell, the data that gave us the confidence to really pursue this aggressively was a Phase II trial we ran in IPF cough. We saw a 75% reduction in daytime cough frequency, 52.5% placebo-adjusted change, and a p-value of less than 0.0001. So very compelling data, all the patient and clinician secondary endpoints lined up and were statistically significant as well, and we'll get more into that. So I started this company with a neurologist, and the whole premise of why we started this company is, this drug is broadly in the opioid class of drugs. I was previously running a company called Penwest.
We had started working on this drug in Phase II development because it was in this subcategory of opioids called mixed agonist-antagonist. This subcategory was designed with all the drug abuse issues in mind, and so if you focus on the left side of this, just a little tutorial, when you think of things like fentanyl or oxycodone or morphine, they're all mu-agonist. This drug actually works through kappa agonism and blocking the mu receptor, so it's an unscheduled opioid. So my Tom, who's my co-founder, and I felt you could get the benefits of opioids, which is good efficacy, good long-term safety without the baggage of addiction. So that sort of was my interest in this category. I would say Tom, as a neurologist, was particularly interested in two things.
One, there's the interplay between the two receptors, which seem to both have an important role to play in hypersensitivity conditions like cough. If you slide to the right and look at the body, the body's very rich in opioid receptors in the center part of the brain, which is why they treat pain. The brain stem, which mediates coughing and breathing, the lungs and the peripheral nerves in the lung and the lung itself are all rich in opioid receptors. So interestingly, if you've ever looked at cough from other companies, many of their agents are all peripherally acting in the lung only, and they've had a hard time getting good strong efficacy.
Because our drug works at the brain stem, which mediates coughing and breathing, you know, all these different pathways ultimately lead up to the brain stem to, for coughing and breathing, so we think it's an important pathway. We, as I mentioned up front, we've studied this drug in a lot of conditions. On the left you can see lots of efficacy data. This drug's worked in every trial we've run. So IPF chronic cough, highly statistically significant. We ran prurigo nodularis trial, Phase IIb, statistically significant, and uremic pruritus as well, statistically significant. We've got a lot of safety data. You can see in the middle it's been in over 1,000 patients, so there's no long-term safety signal to date.
We've also dosed it in 6-month and 1-year trials, and you can see on the right we've laid out the data, which really shows you this drug at a fixed dose has good durability of effect. So we know a lot about it as we head into these, develop, into these clinical trials. So just to frame out the cough opportunity, cough overall is a $10 billion market, and just to be clear, what we're not interested in is what we think of as a productive cough. So if you have a cold or you have asthma and you're trying to cough things out of your lungs, we don't want to interfere with that process. The markets that we are focused on are more what's neurological coughing. So there's something going on in your body. Idiopathic pulmonary fibrosis is a good example.
You have this fibrosing, which is a fancy word for scarring in the lung tissue. It's progressive. Your lung senses something wrong. It sends a signal to the brain stem. Your brain stem basically can do one of two things. It can sort of gasp for air or it can cough. And so the neurological response back is coughing. So we're trying to intervene. If you think of sort of the pain world and how you're trying to intervene on the pain signal, we're trying to intervene on the cough signal. So those, the two markets we're focused on is IPF chronic cough and refractory chronic cough, both non-productive neurological coughs. This looks like a busy slide, but just to break it down, it's the competitive landscape. And on the left is IPF chronic cough, on the right is refractory chronic cough for RCC.
The further out you are in this circle is the earlier stage of development. Going into the middle, the dark circles is approved drugs. As you can see, there's nothing approved. In IPF chronic cough, you can see in that light blue circle, it's essentially Phase IIa, and there's been a lot of failures, and all those little pie slices are different mechanisms. So in IPF chronic cough, we've had the best data and also the most advanced drugs. So we feel excited about the opportunity we have there to be first in class, best in class data. Refractory chronic cough was a busy space sort of three years ago, and you can see, and again, this outer circle, a whole lot of failures of different mechanisms. They've struggled to find things that work. We had two sort of these P2X3s emerge to the center.
You had Merck's gefapixant, which got a complete response letter from the FDA over the holiday, so we'll see where that program goes. And then Bellus had a drug which was acquired by GSK for $2 billion about a year ago. They're in phase 3 trials, but other than that, there's really nothing else out there. So we've targeted this space, we think, with our central mechanism that we have an ability to work more broadly in cough and have a bigger response. So let's delve into each of these indications a little bit. So IPF, idiopathic pulmonary fibrosis, it's an orphan disease, about 140,000 subjects, patients in the U.S. One of the hallmarks of this disease is cough. About 85% of these such patients cough, and they, it's not just a nuisance cough. They can cough up to 1,500 times a day.
The median cough is reported to be 500 times a day. So very bothersome cough. There's some early literature out that this coughing contributes to the overall disease, the inflammation, hospitalizations, exacerbations, etc. So we think it's an important part of this disease management, and it's why we targeted the area. We ran this Phase IIa. It's a randomized double-blind placebo-controlled crossover study. We had about 40 subjects. You can see patients either randomized in on drug. We titrated them up across our whole dose range over three weeks. They washed out for two weeks, then crossed over to the other side. The primary endpoints, that little box down on the right, it's an objective cough monitor, and this has been used in all the cough trials run. It's an accepted endpoint by the agency, and essentially it objectively counts the number of coughs somebody has.
So essentially you're trying to reduce the overall cough count. This is an oral tablet that we have. So these are the basically characteristics of the trial. On the left you can see looks like a typical IPF trial. It's older males. Average age was 74. 84% were males. About half of them were on background antifibrotics, half weren't. We didn't see any difference in our data. And you can see the mean cough frequencies. The primary endpoint was daytime cough frequency because 90% of your cough occurs in the day, but we did also, in a pre-specified way, look at the 24-hour cough count. On the right it's our patient disposition chart. You can work your way down it.
I think importantly we started this trial in late 2019, which, if you remember COVID, that wasn't a great time to be running an IPF trial, so really didn't get sort of up and rolling, and we had to kick a few patients out in the early days. Once we cleared through COVID in 2020, we were able to get this study enrolled and moving along. So this is our primary endpoint. On the left is daytime cough frequency. It's a geometric mean percent change. You can see 75% reduction from drug in three weeks. So if you're somebody that coughed 1,500 times a day, that was a really meaningful reduction for you. 52.5% placebo-adjusted change. The 24-hour cough data looks really similar, roughly 51% placebo-adjusted change. This is actually my favorite chart because it's a responder analysis.
So if you look at the bar graphs, on the left of the bar graph, this is how many people had a 30% reduction, which is considered clinically meaningful. And what you can see here is 97%. So everybody but one person had at least a 30% reduction. When you move right and raise the bar and cut their cough in half, it's still three-quarters of the patients, and the very high bar of 75% reduction is almost half the patients. So, you know, really strong response overall, and I point out on the bottom right you can see the p-value of 0.0001. It's because it was a big drug effect that was in almost everybody. So nice place to start from and proof of concept. So this was all objective cough monitor data I showed you. This slide lays out the patient reported outcomes.
So you would hope that if the cough count is showing such a big reduction in cough, the patient also is detecting that. So we had different daily measurements. The upper left is a cough frequency score. The bottom left is cough severity, breathlessness, and the bottom right is a clinician impression of change. And you can see the blue lines or blue bars are drug. It separates from placebo in a statistically meaningful way. And importantly, if you focus on the upper left chart, it shows you this drug worked really quickly. It was statistically significant by day two. If you look along the bottom of that same chart, you can see we were titrating. So people started at 27 milligrams, went to 54, 108, 162. So the drug worked at the lowest doses and worked quickly.
So it's a good jumping-off point when I show you our next study, which is essentially we dropped the highest dose and we're really doing a proper dose ranging study on the 3 doses in the bottom end of this range. So I can't just show you great efficacy data. I got to show you the other side too. So our safety data, here, you can see typical kind of opioid side effects, CNS kind of side effects, nausea, fatigue, constipation, dizziness, somnolence. Think a couple things that are a hallmark of this drug, and this, this would look the same if I showed you every clinical trial we ran. You can see we've graded them by a level of intensity, so that's what the 1, 2, 3 is. About 95% of these are grade 1 or grade 2, so mild to moderate in intensity.
As you go down, and the other hallmark I would say of this is these tend to come on early on initiation of therapy, so they're more tolerability AE. So you can see here in week 1, which remember when we're titrating is the lowest doses. When people get through those, the AEs start coming down. People get used to the drugs. And you can see across the bottom here, the average duration of effect of these AEs is about 3-6 days. So if people have nausea, it lasts a few days, they get used to the drug, it moves on. So, and we've got sort of tips and tricks of people take it with food, that tends to help, etc. But, you know, this is all part of the central mechanism of the drug.
There are some AEs that go along with it in the early part of dosing. So this is where we're running this trial. We call it the CORAL trial. It's a Phase IIb dose ranging study, 160 subjects, so 40 per arm. I mentioned to you we dropped the highest dose. We didn't think it looked like it was adding much in the efficacy side. Same primary endpoint. It's that VitaloJAK cough monitor. We have moved to the 24-hour cough frequency. I showed you that chart where there wasn't much difference between the daytime and 24-hour. One thing we're going to do, which will come later this year, is when we get 50% of the subjects completed, we are going to do a sample size reestimation. So this is an unblinded statistician outside of the company. We'll recheck our powering assumptions. We'll get one of three answers back.
Either you're fine, keep going, your drug's working, you need to dial in the N a little bit, may need to upsize, or it's futility, and we'll get that answer. So we'll get that read later this year. This is a great tool to use when you're in primarily Phase II and you don't have a lot of powering data so that you don't end up missing it by a little bit. Secondary endpoints are all common, common secondary endpoints. So at a high level, trial started in December 2023. We're going to enroll it over the course of this year. We'll have a sample size reestimation in the second half of this year and full data in the first half of 2025. So moving into refractory chronic cough, we call this our RIVER study.
If you know the refractory chronic cough market, it's a big market, and typically people have some kind of underlying condition which initially triggered coughing, things like asthma, GERD, postnasal drip. The underlying disease gets treated, and there's sort of this hypersensitivity, that sets in and triggers this constant idiopathic cough that goes on. People live with this for years. It's very disruptive. They've really struggled to find anything that treats these patients. You can see here, about 72% of RCC patients are considered uncontrolled. I think another really important aspect of our story, you can see the little circle there, which is a lot of the P2X3s I showed you on that slice, the Bellus drug, the Merck drug, they have only shown efficacy in the highest cough counter. So the greater than 20 cough counters, that's that 29% bucket.
10 to 19 coughs per hour is represented by 44%. In our IPF data, we saw that our drug worked across all those different cough count ranges, and you can see that in that responder chart I showed you. So we think that with our trial, we're targeting the biggest piece of this market, the 75%, both high cough counters and moderate cough counters. So that's essentially what this slide shows you. What we say across the top is we are doing a one-to-one stratification. So in the moderate coughers, the 10 to 19 will have an N of 30, and the severe coughers will also have an N of 30. So this is the trial design. It looks just like the crossover study I just showed you. A lot of data point reads across the bottom. We're essentially titrating up a dose every week.
So at that point in time, we'll recheck their cough counts. I mentioned the stratification. The overall powering of the study, we've overpowered the primary endpoint, which is the N of 60. We only need to see a placebo-adjusted change of about 25% to have stat sig on the total trial here. We did that because we were also trying to get statistical significance on each of the stratified arms. So with a 34% placebo-adjusted change, we will also see statistical significance in each of the stratified arms. Remember in the IPF trial I showed you, we had a 52.5% placebo-adjusted change. So we've tried to be conservative here in our powering, and I think this data is going to be really important for how we move forward.
We initiated this study at the end of last year as well, and we expect data on this trial in the second half of this year. Finally, the last clinical trial we're also underway on, I mentioned to you, this was an opioid. There's been a ton of work done around this, around abusability. I should have mentioned this drug was actually available on the market as a sub-Q injection for acute pain. Our novel sort of step when I was at our prior company is taking this into a twice-a-day oral and doing all the chronic tox work. So there was a lot of sort of work done around abusability long ago, and the drugs remain unscheduled for 30 years by the DEA. We are now running this with our product. We will do this overall comparability of our drug to a Schedule IV, to a placebo.
We hope this is sort of the last step and what we will submit, and hopefully our intention is to keep the drug unscheduled. We've seen no sort of likelihood or drug seeking in our trials. So just our data readouts overall, it's a big year, as I mentioned. So we're underway in our IPF chronic cough trial. Later this year, we'll get the sample size reestimation and first half of next year full data. We're doing some work around respiratory physiology that'll define our patient population for phase three. Refractory chronic cough is underway. We'll read that out the second half of this year, and we'll also have our human abuse potential data in the second half of this year. We fortunately are well funded. We've got about $89 million in cash as of the end of September. We're a small company.
We only have about 25 people, so most of our burn is all clinical costs. That'll cover all of these trials and give us an additional 12 months of runway after. We've got cash that takes us into early 2026. With that, I'm happy to open it up for any questions.
Thank you so much. Okay, I can kick off the questions. I want to start first with IPF. I think it's a really interesting way that you're going about it. I think, you know, when I think classically IPF trials, I'm thinking fibrosis improvement, I'm thinking FVC improvement, things like that. And you're kind of definitely going about it in a different mechanism with targeting the cough.
So can you talk about maybe the differences in how the, those drugs that are being developed for fibrosis improvement versus yours, and how, how, how do those differ in the improvements that those have shown in cough versus how, like the improvements that you guys have seen in IPF?
Yep. So the antifibrotic drugs, either those approved or those being studied, none of them have shown any improvements on the symptoms for patients' cough, dyspnea, anything. Essentially, what those drugs are doing is slowing progression. They're not even improving the disease. They're just slowing how fast you decline. And so typically a lot of patients get diagnosed because the first thing they get is this cough, this dry cough, and they go in and find out they have IPF. The cough gets worse throughout the disease. So you are right, Nicole.
I think they're coming at it from trying to slow the fibrosis, which, you know, it's been shown. There's good publications out that instead of living sort of 3-5 years with IPF, you can extend that to 5-7 years. But as a KOL told me, you know, people essentially go from living 3-5 years of a terrible life to living 5-7 years of, you know, quality of life, not terrible life, but terrible quality of life. What we're trying to do is essentially impact the symptoms, which we think are contributing to the disease as well. So if you're coughing so much, you know, it's contributing to your exacerbations. People get holes in their lungs. They end up hospitalized. So we think if you can settle all that down, people are able to stay more physically active.
They're able to stay more social. We would hope some of that would pull through. Now, our primary endpoint is cough because there's a tried and true path through that that quite frankly is not so hard of a bar as, you know, some of these other areas. We will measure FVC too. The one interesting thing about that, I mean, I hear from KOLs all the time, you're going to improve FVC because if someone's not coughing all day long, their FVC is going to be better. But we're not sure that's really improving the disease. And I'm like, oh, I don't care if that's the endpoint. So, it'll be interesting. We're doing a lot of work in the background about what coughing does to the lung, and we're going to try to put that story together. But you are right.
I think we're approaching it more from a physiologic angle and really more things the patient will be able to measure.
Absolutely. And as a follow-up to that, you asked a lot of my other, or you answered a lot of my follow-up questions, but one more that I have, I guess, on this different mechanism is, so you, as you're with chronic cough, I can imagine that you're causing repeated trauma to the lungs, which does that also implicate or cause fibrosis to worsen over time if it's just the chronic cough? And do you think maybe over a longer period of time after a few years on your drug that maybe you would see from your drug alone an improvement in fibrosis just primarily due to the lack of trauma that is now being induced?
So it's a good question that nobody knows the answer to.
I do think the trauma to the lungs is contributing to things like hospitalizations, exacerbations, which are typically what kills these patients. Whether it's actually contributing to the fibrosis, there's probably no good evidence of that.
Okay.
So no, I think what you're going to do is get at some of these other metrics that contribute to the disease overall.
Fantastic. Thank you. I guess pivoting over to refractory chronic cough. You had mentioned a lot of the different etiologies, that come or that, you know, that cause the chronic cough, like asthma, GERD, bronchitis, things like that. Do those all emerge from the brainstem? Like, can your drug, will you be focusing on a specific subset that have, that comes from specific, you know, etiologies, or does all of them kind of originate within the brainstem?
So I think it's the opposite direction.
They originate in the lung. So there's a trigger in the lung that eventually goes up the spinal cord to the brainstem because that mediates coughing. So, you know, I always joke, all roads lead to Rome. So it doesn't matter what's triggering it, whether it's asthma or bronchiectasis or, you know, GERD, whatever. Once the diseases get treated, that brainstem, it gets what's called hypersensitive. And we've all had that. If you've ever had a cough for like three weeks, it doesn't take much to send you into a coughing fit. You smell something and you're just very hypersensitized. And these people have lived with cough for years. So you're trying to settle that hypersensitization down so that they're not reacting to every trigger that comes through.
Got it. Okay. So, but so all etiologies do, I guess, end up within the brainstem then?
I mean, that's our hypothesis. I think of it a lot like I grew up in the pain world. You know, if you think of pain, and I've had pulmonologists say to me, you know, cough is the lung's version of pain. I think itch is also in the same boat. If you think of the pain world, it doesn't matter if you have pain from cancer or back problems or surgery, it all goes to the brain. That's why opioids are so effective at treating pain signals. We think it's the same way with cough.
Will that be a subgroup analysis within that clinical trial of where the etiologies of where the chronic cough is coming from?
Yeah, we'll have to show that in RCC for sure. What was the medical history on each of these patients?
Was there more of a bias for it to work in other things? I will mention in RCC, this world's been evolving. A really key aspect of RCC is those underlying diseases have been treated and they're not sort of the reason this is going on. So once you sort of treat these underlying diseases and you have the residual cough, that's what you're treating. But yes, we will look at it by medical history.
Okay. Fantastic. Any questions from the audience? Okay. I will ask 1 more. And so, you guys are somewhat approaching within the next year of having your top line data. So I'm going back to IPF. I guess what, what does a Phase III IPF trial look like? How many patients is that going to have to be? How long?
Like, have you guys, I guess it might be a little premature to answer this question, but, I guess what are your thoughts as you're progressing?
Yeah, no, we have a sense. We've been in discussions with the agency and there's a lot of work. Fortunately, there's been a lot of work done in IPF and a lot of work done in chronic cough. So you can sort of pull from both of those. The trials aren't going to be much different size than what we're running now. I'm thinking of those, we're studying 3 doses. I would hope we could pick two. So, you know, from a powering perspective, you're probably, you know, we're running 160 subjects. I'm guessing it'll be roughly the same size, maybe 150 patients. We would like to run two Phase IIIs in parallel.
I think the efficacy read, data read point will be either 3 months or 6 months. That'll be our choice. Our drug seems to work very early and have good durability of effect. So we'll, we'll pick one of those. What I do know, and this comes out of the IPF work, you'll recognize, is that the FDA is going to want 12 months of controlled safety here. So, you know, whether we get all those patients out of these trials or we have to funnel some in through an open label, we will have to get 12 months of controlled safety.
Makes complete sense. Okay. Thank you so much.
Thank you for having us.
Yeah. Thank you so much.