Trevi Therapeutics, Inc. (TRVI) Earnings Call Transcript & Summary

Welcome to this session of the Morgan Stanley Global Healthcare Conference. I'm excited to welcome the team from Trevi. Before I do that, let me read a quick disclosure statement. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. So with that, Jennifer, Farrell, thank you for being here.

Maybe we could just start with an overview of the company for those who might be less familiar, or newer to the story? That would be great.

Yes, happy to do that. And thank you to everyone that came. I see some old friends in the audience. And Judah, thank you to you and Morgan Stanley, our newest relationship, newest analyst. That's great. So Trevi has had a strong year. We are a single-asset company. We have a drug that's broadly in the opioid category but is in a subcategory of mixed agonist-antagonist. We'll probably talk more about that. What's interesting about it is you get the benefits of opioids, good efficacy, good safety without the addiction potential. So the drug has been around. It's been unscheduled. So we can get more into that later. But what's unique about that mechanism is it works both centrally and peripherally. So I'm one of the two cofounders of the company. I co-founded it with the neurologist. Tom, my co-founder, was interested in looking at places opioid biology played an important role outside of pain. And so one of those areas we explored was cough, chronic cough. And Tom was thinking a lot about it as conditions that cause sort of a wind-up neurological phenomenon, which is why the central mechanism is important. That has sort of landed our way towards three legs of the stool that we're building out here, very capital efficient. It's one drug, three indications, all in cough. The first is in chronic cough and idiopathic pulmonary fibrosis. We can get more into the market of that. But you probably know IPF is a tough diagnosis. People typically die in about 3 to 5 years, and 85% of them have chronic cough. So it's a big part of that disease that they struggle with. The second leg of that stool is other interstitial lung diseases outside of IPF, and essentially what they all share in common is fibrosis and cough. So with our strong IPF data we decided that we're also going to bolt on sort of the other half of this equation of non-IPF/ILDs. And then earlier in March, we had also looked at a space called refractory chronic cough, which some of you may know. There's been a lot of companies. I think there's been like 20 assets studied there. All have failed except for the BELLUS/GSK drug, which GSK ended up acquiring BELLUS for that program a couple of years ago for about $2 billion. They are now in late-stage Phase III programs. We think that they -- while they may be first to market, our data was much stronger. So we think we have the ability to be best-in-class. Farrell will talk more about this when we get into it. But commercially, the way we're going to tie all this together is leading with our specialty strategy in pulmonology, high pricing targeted commercial footprint. And in RCC, the way that pulls in because that's a very big patient population as we will go after treatment-resistant patients and maintain that pricing. So again, super focused model. We are heading into Phase III in our IPF program. So our next key milestone is an end of Phase II meeting. We'll look to launch ILD in parallel, and then we've got to do some dose finding work around refractory chronic coughs. So yes, it was a productive year for us. I think we have a strong focus, and I just need to align with the agency and keep moving.

Okay. Great. So maybe we start going a little bit deeper on the competitive landscape. Like you said, there're some drugs in Phase III studies as one approved drug outside the U.S. in refractory chronic cough. How well these drugs work would you say in general? What are patients doing to manage symptoms here?

Farrell?

Yes. So when we look at the competitive landscape in IPF and ILD, really, there's no approved therapies. One thing that we know about the drugs that they're using is even the antifibrotics, they don't benefit the cough. They don't worsen it, but they definitely don't provide a benefit to it. So it's really a wide-open landscape. There's really only one other asset being studied there by BI. That is a peripheral-only mechanism. So getting back to Jennifer's point, the differentiation we have is we work broadly. We work a rapid effect in a large proportion of patients. That mechanism that they're studying has also unfortunately failed in refractory chronic cough with two other companies. When we look at refractory chronic cough, as you mentioned, Judah, gefapixant is approved ex U.S. They had challenges in the U.S. They will not commercialize here in the U.S. And the challenges they really have is this is once again a peripheral mechanism. And it -- it's part of what they try. They try Tessalon Perles, they try all these other therapies, but they really don't work, and they don't last.

Okay. That makes sense. Just thinking about kind of historical chronic cough trials, you've seen significant placebo responses. It does seem to vary based on indication and trial design. But can you talk about placebo responses in chronic cough generally and how you're managing that for Haduvio's development?

Yes. So I'm going to break these into two buckets because in IPF chronic cough, the placebo effect has been pretty well behaved. It's been sort of 15% to 25%. We just saw in our 165 person trial that we had just under 17% placebo response, which is pretty standard, I think. We believe that's because you've actually got fibrosis in the lungs that's triggering this cough. So trying to overcome that with placebo very difficult. Refractory chronic cough has been a big problem. I mean, Merck, which was sort of the first guy over the wall here, had to figure all this out. They saw a 50% placebo response, which is just way too high. And I think there's been a lot learned in refractory chronic cough. I think when Merck ran the study, there was less rigour around making sure all the other sort of comorbidities has been excluded. If asthma has been treated, or GERD has been treated. I think now BELLUS did a nice job of sort of making sure they adjudicated that. They've got the right patients. I think the other big part of this is keeping a tight study. If Jim was here, our development colleague, he would say it's all about getting the right sites, the right patients. I think because these peripheral-only agents have a small effect, they need a lot of patients in their study. I mean -- and GSK is almost up to 1,000 patients. Now we will need nowhere near that. When you do that and you're running two studies. You have to go to a lot of sites, and that's when you sort of lose control of this. So it's not been a problem in IPF. RCC, it's definitely something that's got to be tightened up and paid attention to.

Okay. That makes sense. And you're starting a Phase III IPF program next year. I know you're still in the planning stages, but what can we think of in terms of trial design, maybe relative to the Phase II program?

Yes. So our Phase IIb study is a good comp actually. It was a dose-ranging study. It was 6 weeks long. The primary endpoint was an objective cough monitor. We had several secondaries. When you fast forward to what our pivotal program looks like, it's a little bit of rinse and repeat. It's the same primary endpoint. It will go to 12 weeks instead of 6 weeks. That's what we're proposing to the agency. Same second -- the secondary endpoint we used in that cough severity numerical rating scale will be our key secondary. So a lot of the same things. We also get the ability to tighten it up a bit. We've selected our dose. So not a lot of new learnings here though. I feel like CORAL was a really good study to derisk where we're heading with that.

And can you give us an idea of size of the study relative to CORAL? Again, you mentioned that effect size, which should control...

Yes. No, that's worthy of a discussion because if we only had to power the study based on objective cough count, we would only need about 30 to 40 per arm. So we're only taking one dose forward and placebo. Obviously, we'd never get enough numbers for the safety database. But we also have to hit on our key secondary, which is the cough severity NRS. And we think this is all going to be in play in the end of Phase II meeting. But we think we need to have a responder analysis around that. So that drives the numbers up a bit. When you think about getting enough patients for your safety database, we're planning on about 250 patients per arm -- per study, I'm sorry.

Okay. That's helpful. And then you'll also be initiating a Phase II study. In a new group of patients, like you mentioned, the non-IPF/ILD indication. So what's the incremental opportunity in these ILDs maybe from a patient number perspective? And how similar is the cough to IPF?

Yes. So Farrell, go ahead.

So when you look at IPF, just to ground us in the IPF opportunity, there's about 150,000 patients in the U.S., about 2/3 of them have uncontrolled chronic cough. When you look at non-IPF/ILD, it more than doubles that. So you have about 225,000 patients, and that excludes sarcoidosis because those don't always present as fibrotic lung disease. And about, call it, 50% to 60% have uncontrolled chronic cough. So really, the underpinning of this is that they have a level of fibrosis, and they have chronic cough. When we asked an ad board, we had one at ATS earlier this year with ILD experts. And the first question we asked them is, do these patients cough and does it present differently? And all of them overwhelmingly said, no, these patients have a huge unmet need. There's still nothing being studied. So they present similarly.

Okay. Is there anything from a mechanistic perspective that might make you think that Haduvio wouldn't work in these patients versus working in IPF?

I mean they were pretty adamant. You've already studied these patients. IPF is an ILD, it's fibrosis and cough. I think the biggest risk with this study is making sure they're stable on what other comorbidities they have. There's a broad range of things here that patients can look like. I also think variability will be a little bit of an unknown, maybe more variable. We're going to power around our IPF study. But we had a good discussion around that, that we think that's a risk we're taking. We'll probably build into it for anybody who's followed us for a while. We like to use the sample size re-estimation, which we won't do in IPF. We don't need it anymore. But think in this ILD study midway through, we'll sort of recheck the powering assumptions, make sure there's not something about variability and go from there. So that's probably the biggest risk.

Okay. And maybe can you take a couple of minutes and walk us through clinical development pathways for the non-IPF/ILDs. I think you've talked about potentially marrying it with the IPF study. So maybe if you could just remind us of the interactions with the agency and how that will inform how these programs both move forward?

Yes. So our interactions with the agency to date have all been around our IPF program and pretty early pre-IND kind of discussions and then things along the way as we've been finishing different studies. But the end of Phase II is a really critical meeting. And we had a lot of discussions this summer. We were talking about Dr. Makary and he's saying all the right things, how we want to sort of lean in on that, where is the right place to lean in. What we've decided is we're going to go in and propose two IPF studies, even though I do think there's an argument to do one IPF study, I think because that's rinse and repeat, huge indication, first one across the finish line, we don't want to mess with that. And sometimes FDA, there's no set guidance on when you get away with one study and when you don't. So you always take risk there. I think where we're going to lean in to your question, Judah, is on the non-IPF/ILD. We're going to run that in parallel. That should finish enrolling pretty quickly because it's the same centers you're in. A patient comes in, they either have IPF or ILD in these ILD care centers. So we think we can enroll that quickly, and we're going to talk to the FDA that if that's positive, could we merge that in on the indication statement for cough and interstitial lung disease. If that answer is no for any reason, then ILD just becomes an sNDA and it follows by 10 months. So there's sort of no downside. We're just trying to close that gap if it's possible. I think we're not making the strategy up. Antifibrotics, they typically do one IPF, one ILD. We just didn't want to put our IPF program in any kind of risk, so that's how we're thinking about it.

And just remind me, the sequencing of the two meetings with FDA, the end of Phase II versus what the other type would be, but just the sequencing of those.

Yes. So we, again, all debated sort of what you lead with. We decided to lead with IPF because it's our strongest data set. We have a lot of data. The data is super compelling. We also know the things the FDA was focused on from a safety perspective. They wanted to see drug-drug interaction study with the other antifibrotics. We're finishing that now. They wanted to see our human abuse potential study, which is done. And they've also wanted to see our respiratory physiology study, which we're in the process of and we'll have. On the heels of hopefully, a constructive end of Phase II meeting, we're going to let them know there that we plan to come right back to them to discuss the ILD piece of this and we'll submit the full protocol and ask for a Type C meeting. So we're going to lead with IPF and follow right on the heels of ILD. Refractory chronic cough, we actually don't need to talk to them. We can just sort of keep moving on that program.

Okay. That makes sense. And just speaking of mechanism here, right? I think we've gotten the question on concerns about abuse potential. You're doing the abuse potential study. But what have you seen so far in your studies that could point toward abuse potential or posing of a commercial risk? Or is that less relevant than maybe investors think it might be?

Yes. I always joke to investors, doctors, patients and strategics don't really dig into this. It's investors that worry about it. And I get it. The O-word is a bad word in today's society. I think to answer your question directly; this drug is a known entity. It's been around for decades. It's been unscheduled by the DEA. The reason it's unscheduled is when you think about fentanyl or morphine, those are all new agonists. That's where the addiction comes in. This -- there were four drugs developed to actually get away from addiction. So nalbuphine is a mu antagonist like Suboxone and a kappa agonist for any of you that followed Cara. Neither of those mechanisms have ever been scheduled. So there's good precedence, nalbuphine hasn't been scheduled. We ran our human abuse potential data. We believe it's very supportive of that same profile. I think the last key piece of the puzzle is we'll have to submit what they call AEs of Special Interest from our full clinical development program. That's things like euphoria, hallucinations, et cetera. We've seen very little of that. I mean we've published all of our AEs. It never makes any kind of chart of numbers. I mean, yes, there's one-off things, of course, like we all would have. But yes, nothing there we're really particularly worried about. So feel good about that situation.

Okay. And how are you thinking about, I guess, in terms of scheduling, if you end up in a place where maybe sleep aids are, how do you think that impacts commercial potential or...

Yes, Farrell did a lot of work on that.

Yes. So when we did work in the IPF/ILD space, I mean, this is a terminal disease with a high unmet need. It really doesn't have much impact when we've done our research with prescribers, and we have a patient ad board as well. They care about efficacy and safety first, and we definitely tick both of those boxes. Even if we end up in a Schedule IV, there's minimal restrictions on that. We can still sample. We can do all the activities we need for trial and awareness. When you look at the RCC, I think people normally have a bigger question of does this have a larger impact in that broader population. Especially with our strategy of going to treatment-resistant RCC, we think we minimize that impact because most of them would flow through specialist centers. Maybe you have about a 20% impact, but it's still going to be minimal in that. I mean our base case is this remains unscheduled.

And Farrell, maybe mention the claims database work you did, too.

Yes. When -- there's a nice paper that was published a couple of years ago in the U.S. in the Midwest of the claims database and it shows that in chronic cough broadly, about 71% of prescriptions are opioid-containing cough suppressants today. So these are therapies that are actually probably posing a potential harm to these patients because they do have a level of addiction, codeine, a level of morphine, hydromorphone, there's neuromodulators. They fall in that category today. So we actually have a public health benefit that we could potentially provide by providing this therapy with a lower relative abuse potential.

Okay. Got it. And just thinking, I guess, a bit further about commercial strategy here. You mentioned it's possible IPF and ILD go at similar times. I guess how could that potentially pave the way for RCC? How much overlap is there like you were talking about in terms of centers?

Yes. So IPF/ILD, the nice part is there are ILD centers, so that encapsulates IPF just naturally. There's about 80 of them in the U.S. Pulmonologists would be a primary call point for us, and we'd stay there for that indication. We think we need probably about 50 to 75 reps in order to cover that universe. We've done some work. I think a really nice analog is Verona within that space, right? Verona is covering a much larger call target, about 14,000 physicians with about 125 reps. So we think we're in the right range there, but we'll do some more work. The question, as you say, is then what does RCC mean? As a small single-asset company, we look to stay focused. Pulmonology will be our primary call point. We may look to add one other specialty that's incremental, maybe something like allergists, small, focused specialty that we'd be able to handle ourselves, not incrementally really change the sales footprint. But in that sense, we'd be able to stay at home. Now a multinational may handle that a little bit differently, but we think that we can cover most of the market. About 1/3 of the market is covered there and probably the treatment-resistant patients are there as well.

Okay. Got it. And is pricing a consideration if you add on the RCC indication?

It's less of a consideration in terms of price. So we think we will lead with specialty pricing in IPF and ILD that really is irrespective of if we come to market with IPF first or the combined indication. We've looked at $60,000 to $85,000 in range, and we just continue to see pricing as inelastic. I think the Insmed launch in bronchiectasis with a much larger population at $88,000 is a great benchmark for us, really paves the way. The question on transition to RCC, it's less of pricing because we'd look to take that same specialty price into that space. But in the treatment-resistant space is what other restrictions could we get from payers, quantity limits, we'll take those reauthorizations in order to maintain the specialty price point. There's also one avenue we're looking at RCC where we may interrogate lower dosing, which may be lower QD dosing that gives us a little bit of flexibility in terms of pricing differential, second brand potential. We'll have to see what comes out of that study, but we think it could provide some upside.

Okay. Interesting. Another question we get is just on IP for Haduvio. Does method of use cover both IPF and RCC? How are you thinking about kind of the broad patent family?

Yes. So just broadly, old drugs, so no composition of matter. So we've been from the early days working on method of treatment patent coverage. We have a broad description out there that covers all these various forms of cough. And when we get data, we pulled out the IPF claims, we prosecuted those, actually got all the claims filed with no changes to them. Unfortunately, the whole game in sort of method of treatment is there wasn't -- there weren't -- there isn't prior arch that you're trying to step through. And we all know 10 years ago, there wasn't work going on here, particularly in this class of drugs of mixed agonist-antagonist. So the IPF patent has been issued. We've just pulled out the Track One claims around non-IPF/ILD to get those issued. And RCC is down to the very final sort of question from the examiner, which isn't surprising, which is refractory chronic cough a generic term or a defined term, fair question. So we've got the sort of world-leading expert on that, that's going to get on and explain to him, this is indeed a diagnosis and that should get issued. So those go through 2039. We also are spending time working with our patent counsel clearly about other kind of dose claims that come out of all of our clinical work. And those will just continue to add on to that IP.

Okay. Great. And maybe before we close out the company-specific portion of the questions, can you remind us of cash runway and which catalysts we've discussed that will fund?

Yes. So we raised money in June off of our CORAL data. We have just over $200 million at the end of June. This model is actually quite capital efficient because it's sort of one drug that you're developing, three indications, all in cough. And as Farrell explained, a lot of overlap in IPF/ILD, same centers, sort of very good learning. So anyway, with that money, we can do our two IPF trials, the long-term extension, the non-IPF/ILD study and the refractory chronic cough IIb. We think all that should report out by the second half of '27. And we have cash that runs into late '28, early '29. So we've got some good room to move. So we're coming up with other ideas of how to spend that. There's actually some interesting stuff coming out of the data as we've really dug into it that we may try to dig into and pull out even more.

Okay. Great. I should mention before I get into kind of the mini survey that we're asking all of our management teams. If there are any questions in the room, feel free to raise your hand. We've got microphones that can circulate. All right. So maybe just kind of this mini survey that I mentioned. So biotech does seem to be more exposed to external and macro factors of late. So we're asking each management team the following three thematic questions. First is China's rise in biotech innovation. How are you thinking about your competitive position here? Will this influence R&D or potentially business development strategy, if it's less relevant, that's fine, too.

Yes. No, that's fine. I mean we're a single asset, small 35-person U.S.-based drug development company. Having said that, obviously, we keep our eye on the broader ball. I would say we're not -- our strategy is not to in-license other things. We can create so much value with these indications, and Farrell sort of do the whole walk-down math, but each of these indications can be $1 billion to $2 billion each. So we're talking about a big drug. So we don't need to go look for other things and get distracted. I would also say, and Judah, you may know this even better than I do. But as I understand in China, there's sort of some therapeutic areas like oncology that are a big focus for them. Respiratory to date hasn't been a problem. So I don't really worry about them to date from a competitive perspective. So really not impacting what we're doing.

Okay. Makes sense. The second theme is AI. Would you say Trevi is leveraging AI or thinking about AI potential to disrupt the space in any way?

Yes. So I'll let Farrell answer this because he's much more informed on it than I am. I've made this edict I'm never learning AI. I'm too old.

I mean we actually had a steering committee, IT steering committee meeting yesterday exactly on this topic. I mean we look at AI in two ways. One, how do we make our work more efficient, how do we drive better decision-making. I think it really revolves around that. As we get closer to commercialization, AI will definitely play a part in that in terms of the targeting strategy and commercial strategy itself, it will play an integral role.

Our regulatory team uses it a lot, too, to search regs and what's new and what's coming out. So yes, a lot of use there.

Okay. That makes sense. And last is hopefully most relevant. Just on the regulatory side of things, changes at FDA, MFN pricing, tariffs, anything on the regulatory side of things that is driving internal conversations of the company.

Yes. I mean we watch it all. The obvious one that's going to be hugely impactful for us is FDA. And I think in our mind, there's a question of what the gap is between what Makary says and what's happening in the divisions. Our division, we're in respiratory pulmonology. It's been decimated. Fired the division head, a 1/3 of it's been wiped out. So now having said that, they've met all their deadlines with us. They've come back with clear guidance. So I can't sort of say that we've seen any impact, but our end of Phase II meeting, I think, will be really telling. MFN, we're watching it. I think the reality is it's a small company, if MFN comes into play, we just won't launch in Europe. We'll be a U.S. company. And tariffs, we have no impact. We did a lot of searching around, but we do all our manufacturing here, all of our supply chains are here. So no impact from a tariff perspective.

Awesome. If there are no questions, I think we will leave it there. Thanks again.

Thank you, Judah.

Thank you.