Thanks for joining us. My name is Roanna Ruiz. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to do another really great global healthcare conference session. With me, I have Trevi Therapeutics, and I have Jennifer Good, CEO, and Jim Casella, Chief Development Officer. Thanks so much for joining me.
Thank you for having us. We appreciate it.
Yeah. That's great. So I'll start off with a big picture question before digging into the details. For investors that are refreshing or digging in deeper on the Trevi story, can you just recap, you know, what's been going on with Trevi's core focus up to this point? You've had a bit of news recently too. Like, what are your main goals from going forward this year and beyond too?
Yeah. 2025 was a very transformational year for us. We read out data in our two lead cough programs, so, IPF-related chronic cough and refractory chronic cough. The data was very strong and consistent, big effect early, worked in almost everyone. We were able to sort of springboard off that data and prepare for Phase III in our IPF-related cough program. Roanna mentioned that we just came off our End-of-Phase II meeting with the agency, which is always a good moment to align. You know, you can live in your own world and think everything's great, and then sit down with FDA and realize you've missed something. Jim can talk more about that. He led that effort, but, that was really an important moment for us, I think.
Otherwise, we've just had our head down preparing for clinical trials. Trevi globally, for any of you that don't know the story so well, our lead indication's IPF-related chronic cough. We're also piggybacking onto that the other interstitial lung diseases and their chronic cough and then refractory chronic cough. That's the totality of the story. We can talk more about the markets later. Both all very big opportunities, very little competition, big unmet needs. Excited about what the future holds for us. Jim and I were talking over breakfast, it's hard to believe that we could be two and a half years away from filing.
Yeah.
I've been on this journey for 12 years as a founder.
Yeah
So may actually live to see this drug approved at some point, which I'm excited about.
That's great. I'll dig in with IPF chronic cough first. You had some news about completing an End-of-Phase II meeting with the FDA, the news coming out this past Monday. Maybe you could just recap what are the main themes coming out of that, and thinking about the Phase 3 program going forward, you know, what are the main details that investors should know?
Well, I brought the guy with me, so I'll let Jim do it. He's our Chief Development Officer.
It was a very positive meeting in terms of our ask for the FDA, which typically the Phase II meeting is really about the plan going forward and the path to registration, primarily focused on what type of Phase III trials you need to run in order to get the approval. I think, you know, we went into the meeting, the FDA was very positive in the feedback that they gave us because we submitted a briefing document ahead of time. We asked them certain kinds of questions related to our Phase III program and the path forward to NDA. We had very, very positive and good feedback from them. Really with the key being on alignment of what we really need to do in regards to the Phase three program.
You know, we'd come out of that, we had planned on doing two trials. We came out of that with two trials with greater granularity around what the FDA would be looking for. For example, there's one trial that will be 52 weeks worth of dosing in a placebo-controlled format. The agreement and alignment that we have is that in one trial, we need a 24-week primary efficacy endpoint, and in our second trial, we'll have a 12-week primary efficacy endpoint after some discussion there. I think, you know, the alignment on the nature of the Phase III trials, the kinds of data, the agreement on the primary efficacy endpoint, alignment on the key secondary endpoints that we'll have in there, a lot of those are gonna be patient-reported outcome measures because we are measuring cough.
We measure cough objectively with cough monitoring, but also the secondary endpoints are around cough, quality of life, et cetera. We have really good alignment on that and down into the nitty-gritty detail of how we actually analyze the data.
Yep. Got it. Tagging on to that, so how did FDA feedback sort of shape your approach in selecting these endpoints, both primary and the secondaries? You know, what do you think investors should be watching for? Let's say everything goes well and you report out this data, what would you be most excited about coming out of the Phase III?
I'm most excited about no surprises. I think the key is that we have very, very solid data going into the Phase III program. We've conducted 2 trials in IPF-related cough to date, our CANAL and our CORAL trial. The CORAL trial was the trial that we read out that was a dose-ranging trial. We know that we need to have an objective measure of cough. We have that. We're using the same system that we used in CORAL and that others are using previously. I think we're good there in terms of the primary endpoint. That's very clearly cough monitoring. The secondary endpoints, the FDA is very, very interested in patient-reported outcomes. That's across the board, but this division is highly tuned into what the patient is experiencing.
We have one of our key secondary measures is cough severity in a patient-reported outcome. It's a tool that we modified and developed and validated. We seem to have very good agreement on using that as our first key secondary endpoint. There's some other parameters around that. But I think the key is that we are basing it on the data that we've generated in the past. The FDA agreed that those would be sufficient and adequate for going forward for approvability. I think that's really what we're looking for. I think we are going into these studies with a very good understanding of how our drug works in this patient population. We know the safety side of it, we need to confirm that with longer trials.
We know the efficacy side of it. The FDA's looking for us to show durability of effect. That's why they're interested in something that's a 24-week of fixed dosing. Our second Phase III study, which will be 12 weeks, is a way of showing them that we have reproducibility on the primary efficacy endpoint. It's really, you know, the durability of the effect and the replication of the effect is really the key. I don't think we're gonna see any surprises there.
I would add two more things. Jim has to worry about getting no surprises. I get to worry about the new fun things we get to answer. I mean, I think this drug clearly works in cough. I think we've shown that. You know, Jim needs to run a good trial and not mess it up. I think the couple things that I think are interesting that'll be new for us is we've powered pretty deep into the secondaries because there was a lot of things in our data which we'll end up sharing at ATS, the American Thoracic Society meeting, but around things like dyspnea and other endpoints that matter a lot to these patients that I think we have a pretty good chance of maybe hitting. Think that's exciting. That would broaden sort of this commercial opportunity and also, you know, benefit for the patient.
We also will do the one-year safety, which should start looking at things like, you know, there's always been this feeling that if you can control cough, you know, these patients are sick, they're coughing a lot, that you might see an overall improvement in their well-being. Things like hospitalizations, exacerbations. Jim will look at FVC over time. I think that'll be interesting, that if you can manage cough for a year, what does that look like for the patient? Think there's some cool new learnings that nobody's had an opportunity to look at because nothing's worked in this space.
Nice. Yep. That's very interesting. I noticed you alluded to powering a little bit. Is there anything you can share about powering assumptions, or what are you thinking about how the arms might behave in the Phase 3s that you're planning?
Yeah. I mean, pretty straightforward. I mean, we have a 2-to-1 randomization for active to placebo, and we are at 90% power for our primary endpoint as well as our key secondary endpoint. I think those are pretty straightforward things that we're looking for in the Phase III program. This is a long study. Our power calculations include the expectation of something around a 20% discontinuation rate over time. Those are all factored into the power analysis and to the sizing of the studies.
Yep. Got it. I noticed you also mentioned you got FDA agreement on the remaining Phase I studies needed to support the program and the filing. Could you give a little more detail on the goals and the objectives here?
Yeah. Typically, the Phase I studies are to support labeling, so these are not studies that, you know, have, you know, tremendous impact on the nature of the Phase III, for example, except that one of the studies that the FDA is now actually looking for. We had done a drug-drug interaction study on the antifibrotics at the time, which were pirfenidone and nintedanib. Now that nintedanib has been approved, they're asking that we look at a drug-drug interaction study to understand if there's any effect there with a background of nintedanib. Based on the metabolic profile of our drug and the way it's metabolized in nintedanib, we expect to see no interaction, but we do need to check that box. That's one of the Phase I studies that we'll be doing that they asked for.
We are metabolized, and this gets into the nitty-gritty, but we are metabolized by liver enzyme cytochrome P450, specifically 2C9 and 2C19 isoforms. There are drugs that one may be taking in the marketing environment that could be inhibitors or inducers of that mechanism. I think, you know, we've all become aware of drug-drug interactions over the years, so we'll be looking at whether drugs that induce 2C9 or inhibit 2C9 and 2C19 as part of labeling. Again, these are studies to inform the prescribing physician what to do if somebody's taking a concomitant medication. Then there's also standard studies we need to opine on what happens in people that have various levels of renal impairment or hepatic impairment. Again, very standard labeling types of things. Those were always in our plans.
We put forward a list to the FDA on the kinds of things that we thought would be necessary for the program to support the NDA. Except for, you know, the addition of an inducer study and the nintedanib study, they're in agreement.
Yep. Okay. Great. In terms of the timelines, thinking about IPF cough, chronic cough, like how do you think about the possible readouts like the two Phase III and also the Phase I that you need to look into?
We're gonna give formal guidance kind of in the next couple months. We just got a lot of information last week, so Jim's team's back sort of putting it all on paper. I think what we have said publicly is that we will initiate the bigger study, the 52-week study in the second quarter. Our teams have been busy at work, so we were always prepared to do two studies sort of and tee them up at the same time. Second study should start sort of Q3. Those will come into play. We're planning for about a 12-month enrollment in each. We should get to the 12-week data endpoint by late in 2027 with the bigger study following in 2028. We're gonna sort of dial in on more granularity for everybody around that, but that's kind of the big broad timelines.
Yep. Makes sense. Great. You have your plan. It's laid out for IPF chronic cough, but Haduvio is also being looked at in other indications as well, as you mentioned, so RCC and in ILD chronic cough. Could you give us a little bit of a refresh, like where are you going with those two other indications now that you have a bit more of a clear plan?
Yep. I would just say strategically it's important. We've always wanted to be an IPF-led company. It's a terminal disease, specialty indication, good commercial dynamic set up. The other ILDs make sense. IPF's about half of that problem of fibrosis and cough. The other half is sort of a big bucket of a lot of different comorbidities, but they have this underlying fibrosis and cough. From our perspective, we think it's a similar patient, so we wanna add that on as an sNDA to our program. Jim, maybe you can mention next steps there.
We will talk to the FDA about the nature of that program, the nature of the Phase 2b/3 trial that we'd like to run for non-IPF ILD. Our expectation is that that's our next point of attention and we would like to have that meeting in the Q3 time period, then move on from there. The idea would be that it would be adaptive design. The Phase II part would be a little bit more of a dose ranging just to confirm that these are slightly different patients. They have other types of comorbidities, and then the Phase III design would probably look very similar to what we're running for the Phase III for IPF.
Yep. In RCC, we're doing our proper 2B dose-ranging study. You know, you remember our first 2A proof of concept, very strong data, sort of showed us two things. The drug clearly seemed to work in that design, but we need to move to a parallel arm design now. Sort of the challenge in RCC development has been placebo effect, and that tends to show its head in these parallel arm designs. That's important for us to do. It also appeared in our crossover data that this drug was working at very low doses very quickly, got a huge effect at the lowest dose, sort of very early into the measurement. We need to go back and tease that out a little better in dose ranging.
It may not be the same doses we're seeing in IPF, so it's an important thing for us to understand. That program will also be an sNDA, so once we get the dose figured out, we believe it's one pivotal study, and we should be able to file.
Yep. Got it. I'll jump onto that thinking about RCC for a second. Could you talk a bit more about, you know, the adaptive features that you're considering for the trial and thinking about how Haduvio fits into the treatment paradigm for RCC, assuming that everything works out?
Mm-hmm. The two Bs, if any of you followed us, the CORAL study, it's pretty straightforward. It's, you know, three different dose arms, placebo, and six weeks of dosing. We'll try to sort that out. Not a lot of adaptive designs in that trial. That'll come more in Jim's ILD study, I think. As far as the commercial aspect, that's an important question for us because RCC, just to kinda give you patient numbers, IPF has about 150,000 patients. Two-thirds of them have uncontrolled chronic cough. Think of it as about 100,000 patients. That sort of commands a certain level of pricing and sort of sales force sizing, et cetera. When you think about RCC, that is a very big unmet need. It's 2-3 million patients.
They're seen across a lot of different specialties, and Trevi is not set up to be a big primary care sales company, and we don't wanna pursue that strategy. We are focused on basically treating the patients where nothing else works. They're already taking all kinds of different things now, Tessalon Perles, gabapentin. None of that really works. GlaxoSmithKline is gonna read out Phase III trials later this year. They seem to only work in the most severe coughers, the highest cough counters, so it leaves a whole lot of patients without therapy. We think of that market as how we are going to go after it as basically treatment failure patients and those that are seen primarily by pulmonologists. That gets that number down to still a quite big number of about 650,000-1 million patients.
We'll have to sort that out over time. Yeah, GlaxoSmithKline, for some reason, they don't hit. We're sort of alone in this big, huge market, so, you know, we're just trying to keep our options on the table, but that's how we're approaching it today.
Yep, makes sense. Talking about just competitive landscape, and maybe could you frame how is Haduvio's mechanism really differentiated versus the other mechanisms that are out there? Just kind of, like, big picture, help us understand, like, what's very unique about your program.
I mean, the mechanism's different because all the other programs, there have been roughly 20 drugs studied in RCC particularly and probably about 7 or 8 in IPF. They had all failed or had not gotten consistent data. My co-founder is a neurologist, and he, from sorta 8 years ago, was always chirping at me that cough was a brain problem, not a lung problem. When you look at all those other programs, they were all treating cough peripherally through a certain receptor in the lung. The problem is there's a lot of triggers of cough, so if they happen to be treating the right receptor, I think they get, you know, efficacy. If it's triggered somewhere else, they're not catching that.
What's unique about our mechanism is not only does Haduvio work peripherally in the lung, it works centrally at the brain stem, which mediates coughing and breathing. All those triggers eventually lead to the brain stem, and there had been literature out there that the brain was important. I think our program was the first sort of really robust trial to show, yeah, this is how you're gonna treat this condition. What was the second part of your question, Roanna?
Just thinking about how it fits into the treatment paradigm, how it works.
Oh, yeah, the treatment paradigm. I think in IPF, there's nothing else out there. We've heard from investigators, look, if we have patients that cough, you know, they're on a time clock here of sort of 3-5 years that they will get scripts for this. You know, you're trying to improve their overall quality of life, which of course links to sleep and their ability to be out in public, et cetera. In RCC, I mentioned we are going after sort of this treatment failure paradigm. I think if GlaxoSmithKline, which is really the only other sort of program ahead of us, they'll report out data in the third quarter. If they have positive trials, which I hope they do, I think they'll be great at building this market.
Their drug seems to only work in about 15% of that population, so there's still gonna be a lot of people who need therapy and can get to our medication then.
Yeah.
Yeah.
Great. Sounds good. I also wanna squeeze in a question about the third indication, non-IPF ILD chronic cough. I noticed in some of my doc checks that the prevalence and severity of cough in these ILD populations may actually be higher than people originally think. You know, what are your thoughts on that? How could, let's say, if you're able to get approved in non-IPF ILD chronic cough, like, how could that boost future revenues for Haduvio as well?
We've also done a big literature review on this, and it's not super clear how many of these patients cough. We've done some numbers that it's a bigger denominator, if you will. 228,000 patients and about 50%-60% of them cough, which gets you at roughly the same number as IPF. I think it's equally as big of a challenge. What's interesting, I think, from a commercial perspective, which is also true in the clinical setting, doctors are ILD docs, so they see IPF patients, and they see these non-IPF ILD patients. It's the same call point, it's the same centers from Jim's perspective. I mean, clinically, you're gearing up to basically flip the switch when we're ready to open the ILD protocol, 'cause it's all the same investigators. There's just a lot of leverage off that indication for us once you got IPF nailed down.
Yep. There's a lot that's going on in targeting three large high-unmet indications. Was curious if you could just recap and refresh us on what are you thinking about commercial needs in terms of potentially launching across multiple indications, field force, anything you're able to share about pricing strategy, things like that?
Yeah. A lot more thinking to come there. Our current timelines show filing in late 2028, launch in 2029, so we won't have to really start investing heavily there till 2028. We have started doing some of that prep work, obviously, and I think field force sizing for IPF is not that big. It's sort of 50-75 reps because they're all seen in these ILD care centers. This is US I'm focused on. Also, there's been a lot of nice pricing analogs. You know, the IPF drugs are priced at, I mean, nintedanib last launched at $200,000 a year, so there's a high price. I think the bronchiectasis drug that's also another good comp. That's an ILD. So that's $88,000. We've price-tested $75,000-$125,000, which with really no pushback, so you can assume any number in there.
Good pricing, sort of not a large sales force. I look at, for any of you that followed Verona, COPD was a bigger indication, but it's a very good comp about how you can detail into these pulmonologists, I think, and get a lot of traction with not big sales forces. We sort of are studying what they're doing, what Insmed's doing. I think it's a good playbook for us.
Yep. Could you remind us briefly on your cash runway expectations now that you've got a plan in place for Phase 3s in IPF cough?
Yep. We've been sort of working through all that as Jim sorts out the path forward in all our programs. We've guided into 2028, so we had a nice raise last year. We'll report out our cash numbers. I think as of the end of the third quarter, we had just under $200 million guided into 2028 for that cash. That gets us through most of the readouts now that we have this longer study. We'll have to see. I think it's fair to say somewhere between that now and that readout, we probably wanna put some more cash on the balance sheet because we don't wanna squeak into our last clinical readout on fumes. That's never a good capitalization strategy. We have a CFO who's thinking a lot about that, talks to Jim about it every day.
Yeah.
We'll be able to do that, fortunately, when it's advantageous for us and shareholders.
Okay
Not in a big hurry.
Sounds good. Last question as I get to closing. What do you think the market most underappreciates about the Trevi story today?
Jim, you can give your opinion too, but I don't know. You know, we've had a really good year, I think, of getting the story out. Two or three years ago, people didn't really appreciate cough, and I think the leverage in IPF cough. I think by now, investors now have understood the leverage in this model. I think, probably non-IPF ILD maybe people don't quite understand.
Right
the opportunity there. No, I think people, you know, get it. I think people are waiting for us to get closer to data, but what do you think?
No, I think that's right. I think that, you know, we are really specializing in cough. This common mechanism, this chronic hypersensitivity, which represents chronic cough, we can address that need, and we're seeing it now in these three indications. I think maybe as we all sort of keep on talking about that story, people may appreciate that our mechanism is really well suited to these major, these three major types of cough. I think really we can do a lot of good for the patients there and really show some success. I think maybe that's the percolating part. As coming in last year to the company, I really now appreciate that.
Okay, great. Well, we're at time now, but thank you so much for coming.
Thank you.
This was great.
Okay. Thanks.
Yeah. Thanks for having us.