Leerink Partners 2026 Global Healthcare Conference

My name is Rona Ruiz. I'm one of the senior biotech analysts here at Lyric, and it's my pleasure to do another really great global healthcare conference session. So with me, I have Trevi Therapeutics, and I have Jennifer Good, CEO, and Jim Casella, Chief Development Officer. So thanks so much for joining me.

Thank you for having us. We appreciate it.

Yeah, and that's great. And so I'll start off with a big picture question before digging into the details. And 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 so Trevi came off 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 three in our IPF related cough program. And Roana mentioned that we just came off our end of phase two 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. So Jim can talk more about that. He led that effort. But that was really an important moment for us, I think. And otherwise, we've just had our head down preparing for clinical trials. So Trevi, globally, for any of you that don't know the story so well, our lead indications, IPF-related chronic cough. We're also piggybacking on to that, the other interstitial lung diseases in their chronic cough, and then refractory chronic cough. So that's the totality of the story. We'll talk more about the markets later. All very big opportunities, very little competition, big unmet needs. So excited about what the future holds for us. and Jim and I were talking over breakfast it's hard to believe that we could be two and a half years away from filing. I've been on this journey for 12 years as a founder so may actually live to see this drug approved at some point which I'm excited about. That's great so I'll dig in with

IPF chronic cough first. You recently you had some news about completing an end of phase two meeting with the FDA this the news coming out this past Monday so maybe could you just recap what are the main themes coming out of that and thinking about the phase three 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 so it was a very positive meeting in terms of our ask for the FDA which typically then the phase two meeting is really about the plan going forward and now the path to registration primarily focused on what type of phase three trials you need to run in order to get the approval. So 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 three program and the path forward to NDA. So 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, we 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. So I think, you know, the alignment on the nature of the phase three 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 going to 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 life etc so so we have really really good alignment on that and down into the nitty-gritty

detail of how we actually analyze the data yep got it and tagging on to that so how did fda feedback sort of shape your approach in selecting these endpoints both primary and the secondaries and what do you think investors should be watching for let's say everything goes well you report out this data what would you be most excited about coming out of the phase three uh i'm most excited

about no surprises and i think the key is that we have very very solid data going into the phase three program we've conducted uh two 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 so 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. So 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. So 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, so 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, so 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 is looking for us to show durability of effect. That's why they're interested in something that's a 24 week of fixed dosing. And our second phase three study, which will be 12 weeks, is a way of showing them that We have reproducibility on the primary efficacy endpoint. So it's really the durability of the effect and the replication of the effect is really the key. I don't think we're going to 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. So Jim needs to run a good trial and not mess it up. I think the couple things that I think are interesting that will 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. So I 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. So things like hospitalizations, exacerbations. Jim will look at FVC over time. I think that will be interesting, that if you can manage cough for a year, what does that look like for the patient? So I 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. It's very interesting. And I noticed you alluded to powering a little bit. Is there anything you can share about powering assumptions or what do you think about how the ARMS might behave in the phase threes that you're planning?

So I mean, pretty straightforward. I mean, we have a two to one randomization for active to placebo. and we are at 90% power for our primary endpoint as well as our key secondary endpoints. So I think those are pretty straightforward things that we're looking for in the phase three program. This is a long study. Our power calculations include the expectation of something around a 20% discontinuation rate over time. So those are all factored into the power analysis and to the sizing of the studies.

Yeah. Got it. noticed you you also mentioned you got FDA agreement on the remaining phase one studies needed to support the program and the filing and could you give a little more detail on the goals and the objectives here yeah typically the phase

one studies are to support labeling so these are not studies that you know have you know tremendous impact on the nature of the phase three for example except the one of the studies that the FDA is out actually looking for we had done a drug drug interaction study on the antifibrotics at the time which were with perfedadone and intentative, now that Neurodomilast has been approved, they're asking that we look at drug-drug interaction study to understand if there's any effect there with a background on Neurodomilast. Based on the metabolic profile of our drug and the way it's metabolized in Neurodomilast, we expect to see no interaction, but we do need to check that box. So that's one of the phase one 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 enzymes, cytochrome P450, specifically 2C9 and 2C19 isoforms. So there are drugs that one may be taking in the marketing environment that could be inhibitors or inducers of that mechanism. I think 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. And 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. So 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, and except for the addition of an inducer study and the neurodome last study, they're in agreement.

Yep. Okay, great. And in terms of the timelines, thinking about IPF cough, chronic cough, how do you think about the possible readouts, like the two phase threes and also the phase ones that you need to look into?

So we're going to give formal guidance kind of in the next couple of 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 in TM off at the same time. Second study should start sort of Q3. So those will come into play. We're planning for about a 12 month enrollment in each. So we should get to the 12-week data endpoint by late in 27 with the bigger study following in 28. But we're going to sort of dial in on more granularity for everybody around that. But that's kind of the big, broad timeline.

Yep. Makes sense. Great. And so you have your plan. It's laid out for IPF chronic cough, but Heduvio is also being looked at in other indications as well, as you mentioned. So RCC and an ILD chronic cough. So could you give us a little bit of a refresh, like where are you going with those two other indications now that you have been more of a clear plan yeah and 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 and so we're basically the other ILDs makes sense IPFs 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 so So from our perspective, we think it's a similar patient. So we want to add that on as an SNDA to our program, Jim, maybe you can mention next steps

there. Yeah. So we will talk to the FDA about the nature of that program, the nature of the phase 2b3 trial that we'd like to run for non-IPF ILD. Our expectation is that now 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 but the idea would be that it would be adaptive design the phase two 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 redesign would probably look very similar to what we're running for the phase three for ipf

and then 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, so 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 so we need to go back and tease that out a little better in dose ranging it may not be the same dose as 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 got it and 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. So the 2Bs, 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, so we'll try to sort that out. So 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 Just to kind of give you patient numbers, IPF has about 150,000 patients, two-thirds of them have uncontrolled chronic cough, so 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 two to three 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 want to pursue that strategy. So we are focused on basically treating the patients where nothing else works. They're already taking all kinds of different things now. Teslon pearls, gabapentin, none of that really works. Glaxo is going to read out phase three 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. So we think of that market as how we are going to go after it as basically treatment failure patients. patients and those that are seen primarily by pulmonologists. That gets that number down to still quite a big number of about 650,000 to a million patients. So we'll have to sort that out over time. Yeah, and then Glaxo, if 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. And 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 and just kind of like big picture help us understand like what's very unique about

your program I mean the mechanisms different because all the other programs there had been roughly 20 drugs studied in RCC particularly and probably about seven or eight and IPF they had all failed and or had not gotten consistent data. And my co-founder is a neurologist, and he from sort of eight years ago was always chirping at me that cough was a brain problem, not a lung problem. So 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. But if it's triggered somewhere else, they're not catching that. What's unique about our mechanism is not only does Hiduvio work peripherally in the lung, it works centrally at the brain stem which mediates coughing and breathing. So 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 going to treat this condition. What was the second part of your question, Rowena?

Just thinking about how it fits in the treatment paradigm.

Oh, yeah, the treatment paradigm. So I think in IPF there's nothing else out there. So We've heard from investigators, look, if we have patients that cough, you know, they're on a time clock here of sort of three to five 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 Glaxo, which is really the only other sort of program ahead of us, they'll report out data in the third quarter. if they're if they have a positive trial if they have positive trials which I hope they do I think they'll be great at building this market but their drug seems to only work in about 15% of that population so there's still going to be a lot of people who need therapy and can get to our medication then so yeah great

sounds good and I also want to squeeze in a question about the the third indication non-IPF ILD chronic cough and 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 so you know what are your thoughts on that and 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 Hiduvio as well yeah so

we've also done a big literature review on this and it's it's not super clear how many of these patients cough we've done some numbers that there's it's a bigger denominator, if you will, 228,000 patients and about 50% to 60% of them cough, which gets you at roughly the same number as IPF. I think, yeah, so 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. So it's the same call point, it's the same centers from Jim's perspective, I mean, clinically, gearing up to basically flip the switch when we're ready to open the ild protocol because it's all the same investigators so there's just a lot of leverage off that indication for us once you got ipf nailed

down yep yep so there's a lot that's going on and targeting three large high on many 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 to share about pricing strategy things like that yeah so a lot more thinking to

come there we our current timeline show filing in late 28 launch in 29 so we won't have to really start investing heavily there till 28 but 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 to 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, Narendromalas launched at $200,000 a year, so there's a high price. And I think the bronchiectasis drug med is also another good comp. That's an ILD. So that's $88,000. We've price tested $75,000 to $125,000 with really no pushback. So you can assume any number in there. But good pricing, sort of not a large sales force. I look at, for any of you that followed Verona, COPD 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 so we sort of are studying what they're doing what insmed is doing i think it's a good playbook for us yep yep and could you

remind us briefly on your your cash runway expectations now that you've got a plan in

place for phase threes in ipf cough yep and we've been sort of working through all that as jim sorts out the past forward and all our programs we've guided into 2028 so we had a nice raise last year. We've got, 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. So we'll have to see. I think it's fair to say somewhere between that now and that readout, we probably want to put some more cash on the balance sheet because we don't want to ski into our last clinical readout on fumes. That's never a good capitalization strategy. So we have a CFO who's thinking a lot about that, talks to Jim about it every day, but we'll be able to do that, fortunately, when it's advantageous for us and

shareholders in a big hurry. Sounds good. And 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 CoF and I think the leverage in IPF CoF 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 the opportunity there but 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 I think

that's right I think that you know there's a we are really specializing in cough we 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 so 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 majors these three major types of cough and I think really we can do a lot of good for the patients there and really show some success but I think think maybe that's the percolating part that's 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 this is great thanks for having us