Everyone, to the final day of the Cantor Global Healthcare Conference. My name is Jennifer Kim. I'm one of the biotech analysts at Cantor. I'm pleased to introduce Trevi Therapeutics for their presentation. We have with us, Jennifer Good, CEO. Jennifer, whenever you're ready, you can get started.
Thank you, and thanks to Cantor for having us. We appreciate it. I'm joined by my colleague Farrell Simon, who's our Chief Commercial Officer, and thanks to you guys for getting up early for an early morning presentation. I have about 20 minutes of slides, and then if you do have any questions, happy to answer them. Trevi Therapeutics is a single-asset company. We are focused on serious chronic cough conditions. We have two lead indications, chronic cough and idiopathic pulmonary fibrosis and refractory chronic cough. Both are very big markets, very big unmet needs. I'll spend more time talking about that. We're also doing a couple key phase I studies this year. We're finishing up some respiratory physiology work I'll touch on briefly at the end, and also some human abuse work that's also reporting out in December.
We had some really strong data report out in late 2022 in IPF cough, and we'll talk more about it, but it's been a really difficult area. And essentially, what the data will show you, I'll go through it in more detail, is we saw a 75% reduction in chronic cough in three weeks, and the drug worked in everybody but one patient. So primary endpoint was very statistically significant, p-value of less than 0.0001, and all the secondary endpoints, both patient-reported and physician-reported outcomes, lined up. So from that, we spring boarded into expanding our cough focus. So the mechanism of action, there's a great link with our drug and the mechanism of action of what we're pursuing. And this compound actually was in a company that I ran prior to this, which was acquired by our strategic partner.
The chief medical officer there and I were both interested in this compound, and I'll take you through why. And so when the transaction closed in twenty ten, Tom, our neurologist, and myself went back and actually bought this compound out ourselves and started Trevi around it. This drug is broadly in the opioid class, but it's interesting because it's the only unscheduled opioid. And the reason the drug is unscheduled is 'cause it primarily works at kappa. Instead of when you think of things like morphine, fentanyl, those are all mu agonists. This is a kappa agonist and a mu antagonist, so it blocks the mu receptor and agonizes at kappa. Tom, my neurologist co-founder, had been thinking about opioid biology for a while and thought that it had broad applicability beyond just the whole pain world.
It's interesting 'cause endogenous opioids are rich in the body, and they're rich in the brain, the brain stem, which mediates coughing and breathing, the spinal cord, the lungs, and actually the skin. Tom and I were interested in pursuing essentially this unscheduled opioid in non-pain indications. That's been sort of the whole crux of how we started Trevi. Over the course of sort of the last nine or ten years, we've looked at this in several indications. You can see on the left, we've looked at it in severe pruritus conditions, things like uremic pruritus, prurigo nodularis. I mentioned the cough study. What these all have in common is they're broadly hypersensitivity disorders, and I'll sort of take you more through that. The drug has worked in all of these conditions. So Newsflash, opioids have good efficacy. It's why they've been around for a hundred years.
They work. We also have a lot of clinical experience and a big safety database, so we've had it in over a thousand subjects. We've dosed two hundred and seventy for up to six months and almost a hundred patients up to a year. We have not seen any tachyphylaxis, so we know the drug has no safety signals that we've seen to date. We know it's been successful, had good efficacy in multiple clinical indications, and good durability of effect. So from there, we springboard into our cough strategy, and this is just a... It looks busy, but it's easy to orient to. This is a competitive landscape chart. On the left is IPF chronic cough, on the right is refractory chronic cough.
Just to start on the IPF side, that had been an area that people looking at cough had sort of left the space because it became a little bit of this lore that these were really difficult patients. It's an end-of-life disease. It's a progressive fibrotic sort of lung progression, and it was just too hard. You were trying to hit a moving target of patients who were essentially had about three to five years to live. We ran the study because we felt our mechanism, which when I showed you that body chart, what was happening is you had this fibrosis going on in the lungs, signal going up to the brain stem, which mediates coughing and breathing, and you were getting this neurological response of this cough. And that's what I mentioned, we had good data.
There's been multiple failures in this space, and at the outer circles are sort of early in development, the center is approval, and you can see in that light blue circle, which represents phase II, a lot of red dots. Those are all things which have been tried and failed. The little pie slices are different mechanisms, and I think what's unique about our compound is our compound is not only works peripherally in the lung, which is where all the rest of those, compounds were trying to address this problem, but it works centrally at the brain stem, which mediates coughing and breathing, and I think that's what makes our approach unique. When you slide to the right side of this slide, that's refractory chronic cough, and some of you may know this space. Merck, you can see in the center there, got very close.
They did end up getting two complete response letters, and a little company called Bellus, which worked in refractory chronic cough, was acquired by GSK a little over a year ago for $2 billion. But you can see, again, similar story, this sort of phase II-A band here, a lot of failures by big companies. You can see a lot of big pharma names in there, and our belief is it's 'cause they were all trying to deal with this very severe condition, which is primarily a brain issue or hypersensitivity issue, by going at it through the lung, and that's again, where we think we can win in this space.... So let's talk about each of these patient groups. I'm sure a lot of you are aware of Idiopathic Pulmonary Fibrosis.
It is an end-of-life disease, tends to be males, sort of in their mid-seventies. It's very akin to a cancer diagnosis. From time of diagnosis, people typically live about three to five years. There have been two antifibrotics that have been developed by Boehringer Ingelheim and Roche. Those are both very big drugs, priced at about $125,000 each. They, you know, they're $2-$3 billion drugs. All they do is slow the disease progression, so they don't reverse the fibrosis going on in the lungs, which is essentially a fancy word for scarring. All they do is slow that slope. So instead of three to five years, you may live five to seven years.
What they also don't do is improve the quality of life for any of these patients, and you can see across the bottom, about 85% of these patients suffer from cough, and it's this neurological cough, and it's not a little bit of cough. Sort of on average, these patients have 200-500 times they cough a day, and we had people in our study up to 1,500 times a day. So you can imagine sort of in this post-COVID world, trying to live with that. So these people get very isolated. You know, they don't go out. It's hard to talk on the phone. It's hard to have conversations. So they're at end of life, and it's a very isolating, lonely symptom. So when you talk to these patients and interview them, this chronically comes up as one of their chief complaints.
The other important part of this story, though, is we're not just trying to deal with sort of a really severe symptom here. There's also been literature and a belief that this coughing is leading to inflammation of the lungs. It's tied to what's called pneumothorax, which are little holes in the lungs. It's tied to exacerbations. People end up in the hospital. So there's also a belief that if you can settle this cough down, that people will be able to stay more active. They'll be able to stay more social, and the disease overall, they'll do better. So I mentioned to you antifibrotics. So everyone doing IPF development is trying to slow disease progression. We're trying to deal with the most severe symptoms that physiologically are contributing to the disease. This was our phase II trial that we ran.
Everybody in cough runs this sort of accepted phase II crossover design, where you essentially randomize in on either drug or placebo. You were dosed across our full dose range for three weeks, washed out for two weeks, went to the other side. A lot of power in crossover designs because you're your own control. The primary endpoint here is pretty well established in cough. It's that little device down in the bottom right. It's called a Vitalograph monitor. You essentially have a chest sensor on the monitor, and it physically counts the number of times you cough. So it's an objective measure. Primary endpoint here is a mean change, so you know, as a drug developer, that's always a bar that's nice to clear. We do have a twice-a-day oral tablet, so it's an advantageous delivery system for patients, obviously.
These are the baseline characteristics on the left. I mentioned to you, this is a primarily male population. It looks like an IPF population. 84% male, sort of mean age of about 74. About half of them were on background antifibrotics, these, these other drugs I mentioned. We've published the data. It didn't matter if you were on antifibrotics or not. We saw strong responses in both groups, and you can see sort of the mean cough range here of 28. Big range. This is per hour, so cough counts, baseline cough counts of 28 per hour. So the daytime cough, you do 28 by 12 to get daily cough, the twenty-four-hour, you do times 24. But a big range, anywhere from 3 to sort of 92, and that was this range up to sort of 1,500 people.
You can see on the right how this study sort of rolled out. We were running this during COVID, which, as you might imagine, studying IPF patients in the heat of COVID was a challenge. So there was a couple times we had to shut the study down and send everybody back home, kick them out because they couldn't be going to their visits. But we managed to get to the end. The data I'm gonna show you is on the full analysis set, which is essentially, just to go back to the study design, anyone that fully completed one of the two treatment periods is in the full analysis set. We have also presented the full completer, so people that went through both sides. The data's the same, sort of nothing to see there. This is a lot of efficacy data. I'm gonna make it simple.
We've published a lot of it. It's been in the New England Journal of Medicine, so you can go on our website and actually read it for yourself. But the story that it ends up telling, the primary endpoint is up in the upper left. That's basically the mean change on that baseline cough count monitor. So the monitor, you wear it at the beginning, you wear it at the end, and we see what happens to your cough. And what you can see here is on daytime cough frequency, we had a 75% reduction in cough, 22% placebo effect, so significant reduction. We also had a pre-specified endpoint of looking at 24-hour cough counts. You can see the data's the same. So whether you just look at the daytime, where most of the cough occurs, or you look at the full day, very significant reduction.
When you slide down to the bottom left, that starts to get into the patient-reported outcome, so how frequently did you cough today? And you wanna make sure that just because this monitor's counting that you're coughing less, the patient also can feel that difference. And what you see in the bottom left here is drug starts separating from placebo, drug is always blue on these slides, basically right away off the first dose. So there's a direct response, and I think about, again, the pain world. When you have back pain and you take an opioid, your back pain goes away. There's a direct response, and that seems to be happening in cough. You're coughing, you take our drug, your cough starts going away. We've published also the data that by day three, this was statistically significantly separated from placebo.
So big effect, works very quickly for the patient. The upper right's an important chart, and that's essentially the responder analysis. So, you know, 30% is considered clinically meaningful here, a 30% reduction in your cough. And what you can see here is that 97% bar. That represents everybody in the study except one subject. So everybody had this kind of response, and when you keep raising that responder analysis, cutting it in half, it's still three-quarters of the patients, or reducing cough by 75%, it's 41%. So again, back to the story, big effect, came on early in almost everybody. And then the bottom right is just another way people are starting to think about cough. It probably won't surprise you, you don't sort of evenly cough, you know, 200 times throughout the day.
You have these massive coughing bouts, and it's believed that that's probably where a lot of the damage is occurring to patients when you have these hard coughing bouts. So there's starting to be this movement towards starting to look at the reduction in cough bouts, and won't surprise you that when you have this strong of efficacy data, you can sort of cut it any way, and you see good separation. So that's the efficacy side of the equation. The adverse event side, this is a centrally acting drug. So you see typical, honestly, typical adverse events you see with most drugs, things like nausea, fatigue, somnolence, dizziness, some headaches. I think there's two sort of hallmark characteristics of what we see, having run this drug in a thousand people. One, we've categorized these by the CTC grading code of mild, moderate, severe.
You can see 95% of these adverse events are mild to moderate. So, you know, these are not severe incidences. The mild incidences, the definition is they have no impact on your day. You're sort of vaguely aware of them. The other hallmark of this is, this is about tolerability. So you tend to see these. You can see on the right, we've broke down when these occur between week one, two, and three, and remember, we're starting at the lowest dose and going up to the highest dose over the three-week interval, and so they mostly occur at the lowest dose when you start the dosing. After, you can see across the bottom right, they tend to only last a few days. Within three to six days, they dissipate and look like placebo.
So we've done a really good job, I think, in these studies of making sure patients understand that. Some sort of tips and tricks you can do to manage that first week. Fortunately, as I showed you, the cough is also coming down quite significantly, but that is sort of the overall profile of the drug. So we are now into a phase II-B study. We call it our CORAL study. It's 160 subjects, and what we're trying to do is do a proper dose-ranging study. As you can see back in this slide, just the efficacy slide to show you in the bottom left, you can see across the very bottom, the dosing, and at 27 milligrams, we saw a huge response, so, which sort of carried on through 108.
When you get out to the 162 milligram, I don't know if you guys can see that over on the bottom right here, there's really not much of an effect carrying on. So as we got into this phase II-B study, we dropped the highest dose, and we're really interrogating the lower end of this dose range. That's against placebo, six-week study. Otherwise, we're essentially replicating it. Same primary endpoints, mostly the same secondary endpoints. The one thing we did build in here is a sample size re-estimation. You can see here halfway through the study... I think I'm hitting the wall and not the slide. Because there hasn't been a lot of success in cough studies, there's been two other studies run, both of which failed. We didn't have a lot of data to power the study from.
So there's a methodology you can use, which is, you pre-specify it. When we get halfway through enrollment, those 80 people finish the study, we have an unblinded statistician outside the company that'll recheck all the powering assumptions, so drug effect, variability in the study, any discontinuations, and we get one of three answers back. The first one is, "You're fine. Carry on with your original N of 160." The second one is, "Your drug's working, but you need to dial in the N," and we pre-specified a range that that could be in, and so we'll get a number. It could be 200, it could be 210. So we'll see what that is. Or, "You're outside of this pre-specified range," which is basically another way of thinking about the drug's futile on your own assumptions.
We are coming up on that read, and what you're gonna see at the end of this presentation is we're sort of on the cusp of a whole lot of data. So this is one key readout that we'll have by the end of this year, which is a halfway look at this study. So certainly from where I sit, that's important data. Switching to our other indication, refractory chronic cough. We've called it RIVER. Refractory chronic cough is a big unmet need. There's chronic cough's a big problem in the U.S., or in the world, actually. About 5%-10% of people are estimated to have chronic coughing, which is a cough longer than eight weeks. Refractory chronic cough is defined as fundamentally, it's a hypersensitivity disorder. So people have some kind of underlying trigger. They start coughing.
Whatever the underlying disease was, things like asthma, GERD, get treated, and that cough continues on, and it's a serious cough. It looks a lot like the numbers I showed you in IPF. The addressable patient market in RCC is estimated to be about two to three million patients that are moderate to severe, and about 72% of those patients are uncontrolled, so big impact on their quality of life, no treatment options approved for them. It continues to be a big unmet need, and that was that very busy, competitive chart I showed you, and it's why a lot of big pharma was chasing that, because they recognize the opportunity here.
It's been interesting, 'cause there's basically one category of drugs that was the Merck compound and the Bellus compound I pointed out, which is now part of GSK, that made their way to the middle, and it's - they're called P2X3 antagonists. The challenge with the P2X3 antagonists is because they only work peripherally in the lung, they've had to enrich their studies, the GSK study has done this, for only the highest cough counters. It's really the way - only way they've been able to tease out statistical significance. The problem is, the highest cough counters are only that 29% blue bar, so that's greater than 20 coughs per hour. The biggest part of this market is what's considered moderate coughers, so 10 to 19 times an hour, which, as the KOLs always remind me, is still a lot of coughing. Again, multiply by 24.
So that, that's still a big unmet need here. Neither Merck or GSK's compound showed any impact in that sort of moderate category. This is relevant as I show you our study design, because we think back to our mechanism. Because we're working centrally, so it doesn't matter where your cough gets triggered, it's all gonna end up at the brainstem, and that's where our drug is working. We think we should be able to treat cough broadly across cough counts. So same study design I just showed you, this two-way crossover design, three weeks. We did a three-week washout here. You go to the other side. We have across the bottom, you can see the green arrows. Those are all the little VitaloJAK readings we're gonna take along throughout the study. Same kind of data you just saw.
I think the one unique thing here we're doing is the overall N is 60 subjects, which is powered for a 25% placebo-adjusted change, which is a pretty low bar when you think about our IPF data, which was north of 50% placebo-adjusted change. The reason we did that is we wanted to do a 1-to-1 stratification of the cough count. So we have 30 patients in this 10 to 19, those moderate coughers, and 30 people in the greater than 20. Now, we're coming up on the end of this study, and as I've sort of warned investors on our last earnings call, those arms aren't perfectly in balance, so at some time we're gonna cut it. We think we've sort of endeavored to get equal arms there and be able to understand, does our drug work in that moderate category?
So that study's almost fully enrolled, and we'll report out data in the second half of this year. Although I have sort of signaled to investors that we may hold this for a month or two to try to let those arms get more in balance, which may push it into early next year. So my last slide, to wrap this up, as I mentioned early on, we have a lot of data coming. We have our phase II-B study with in IPF, sample size re-estimation by year-end, which will be a really good peek under the tent as to how that's going. Expected top line in the first half of next year. I mentioned early on, we're doing some phase I work, trying to understand the respiratory physiology of these IPF patients. They're a very sick group of people.
That's more about defining the phase III population. Some really interesting science is gonna come out of that, I think, about what is cough doing to these patients when they're coughing. We've got them on a lot of monitors. Refractory chronic cough we just talked about. It's coming by year-end or early next year. And our human abuse potential, which again, back to sort of the mechanism, this drug's been unscheduled for decades, but there was some new guidance out in 2017 that required these human abuse potential studies. So we have to bring it up to sort of the current standard. There'd been a lot of work done prior. So we're finishing that study. That data we'll also report out by year-end, and we'll be good to get out, and people can look at it themselves. We have a strong balance sheet.
We've had good support from investors. We have just under $70 million in cash at the end of June. That takes us into early 2026. As you can see here, that's roughly 12 months beyond all our data reporting out. So, we have a good cash position and just heads down, moving towards data. So with that, I'll take any questions. Yes, Jennifer?
First of all, thank you for the presentation. I have a couple questions. Thinking about the public data, but also as well, can you just walk through the timeline for the, if there's an adjustment to be made?
Yeah. Thank you for that question. The best guidance I give people. She's asking if the sample size re-estimation makes us upsize, what does that sort of mean for us? And the first of all, the bracketed N that we've put in the protocol is anywhere from the planned sample size of 160, which we think we've been conservative in, actually. Just to sort of frame that, we've assumed a 36% placebo-adjusted change. Again, remember, the data I showed you was 50%, so we've built room in there. But it can go all the way up to 400, so we could end up anywhere between 160-400.
I think the most likely scenario is you end up somewhere, if you have to upsize, in the 200-220 range, so it's another 10-15 subjects per arm. To try to give you a sense of what that means for us as a company, we are enrolling roughly 20 people a month at this point. We're sort of hitting full stride, and so you can kind of do the math on whatever you assume. I mean, if you assume another, call it 60 patients, 'cause it's easy, it's another approximately 3 months. So, yeah, and we would have the cash to cover that. I mean, if we have to upsize to 400, then we'll have to sort of deal with that but...
And then thinking about the progress study, the fluctuation, any updates you'd like on what we're doing?
Yeah. So we haven't gotten into which arm and how many we have. So I would say that it was good to hold it because we are closing in on the arm that was open, and we're trying to fill up. I'm not sure we'll get all the way to 30 in one of the two arms, but again, we had a pretty conservative placebo-adjusted change. It was 34% in each arm to have stat sig, which is an exploratory endpoint. So really, what we want to try to see is: is this drug working in both these arms so that we know how to set up the inclusion/exclusion criteria for our next study. So I feel comfortable we'll be able to do that.
... into the opportunity for the moderate participation. What kind of numbers are you getting at, and how much people will use the access to education?
Yeah. Since I have my Chief Commercial Officer here, Farrell, why don't you answer that? You can come on up here and use the mic, yeah.
Thank you for the question. So when we look at pricing dynamics across the categories, because I think that's the, one of the most important pieces, is IPF is our lead indication. With IPF being the lead indication, that is gonna set specialty pricing dynamics, and then within even a broader ILD category, that still maintains those pricing dynamics. So with RCC coming after those, call it launches, our strategy right now is, you're gonna be able to access those patients who are on the most severe end of refractory chronic cough, and by targeting that subsegment of the RCC market, you're gonna maintain specialty pricing. So I don't think less of the moderate to severs as any different. They're still an RCC patient who is most severe and not being treated, and still has a high level of unmet need.
Yeah, and severe is not tied to cough.
Right.
It's really tied to no treatments working for you. So, Robert, I know you were trying to jump in here.
Yeah, I had a couple of questions. One, and it's sort of related to side effects and nausea. Have you had any subjective withdrawals?
We have, actually. I kind of skipped past that slide, but, let me just take you back so you can see it fully. We always lay that out. So if you see here on the bottom right, we talk about adverse events. I don't think this is getting... due to withdrawal, basically adverse events due to drug, which is that 14.6% number. So roughly in the study, we estimate that was 15%-16%. I will say, too, it seemed like you knew opioids. You were sort of nodding with me on a few things when I made points. The literature out there around sort of opioids and centrally acting drugs, not just opioids, is you tend to have discontinuation rates somewhere around that 15%.
And for any of you who have ever had dental work or whatever, some people just don't tolerate these drugs, and there's not much you can do. Then there's a whole class, whole group of people that do just fine on them, so.
Yeah, I mean, you don't have constipation or complication.
Yeah, we haven't seen that a lot with our drug. I think it's 'cause it's more kappa than mu.
Yeah, that's what I think. But the other aspect of this is just, do you have dose titration here, or is that something you're thinking about?
Yeah.
If it acts like other opioids, does that mean that changes in expression?
We do. We titrate in every study, and you're exactly right. You can't just stick someone on the highest dose or you're gonna get... They don't do so well. So you tend to start low, titrate them up. That's one of the real ways you maintain people through the study. So you can see here there's two weeks of titration and then four weeks of fixed dosing. Even the two crossover designs I showed you, those were all titrating up across our dose range.
And you still get, you have-
Yeah.
Because my last question, which is related to the last question on pricing, is thinking longer term.
Mm-hmm.
I was a kid. I was young enough to have terpin hydrate codeine, and it followed me and stuff, and then because it had opium.
Oh, Codeine, yeah.
It was the best. Of course, it was also...
Mm-hmm.
So one could foresee where a molecule like this become broader reach, although not at the price point that you have this, but is this something that you're thinking about as a different, probably with the dose it's hiding? Is there a place where there's in the future for, like, a prescription cough medicine that could be used for all the zillions of people who have the flu or something, and need something that's popping-
Mm-hmm.
Obviously, priced differently, but still protecting your special?
You know, it's been interesting since I've started this company. This drug works in a lot of conditions, and we get all the time. I've had a lot of the key thought leaders, the doctors say: "What about long COVID? There's a lot of coughing." Other interstitial lung diseases, which we are looking at. I think, Robert, part of what we need to do as a small company is focus in. These are two very big. But the answer is yes. There's a lot of cough this probably works in. Now, what, the cough we don't want to interfere in, just to delineate, is any kind of productive cough. Which you were probably taking codeine because you had a cold or a virus, which is clearing your lungs.
So you don't wanna interfere on that process, but there's a whole lot of coughing that's neurological, and that's really where we would target our efforts. But focus. It's, it's intriguing because we probably work in a lot of things, but I think we gotta get these two done.