TRVI - NASDAQ

Good afternoon, and welcome to the Trevi Therapeutics Third Quarter 2025 Earnings Conference Call. At this time, please press one on your phone. Please note this event is being recorded. Various remarks that management makes during this conference call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by the forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent quarterly report on Form 10-K, which the company filed with the SEC this afternoon. In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so if its views change. I would now like to turn the conference over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for our third quarter 2025 earnings call and business update. Joining me today on this call are my colleagues, Dr. James Cassella, our Chief Development Officer, and Farrell Simon, our Chief Commercial Officer. I will make some comments on the business and financial results, then the team is happy to answer any questions you may have. The first half of this year was a major inflection point for Trevi Therapeutics, Inc. With positive data readouts in both the CORAL trial for chronic cough in patients with idiopathic pulmonary fibrosis or IPF and the RIVER trial for patients with refractory chronic cough or RCC. We recently presented these results at CHEST, and it was great to see the interest from leading thought leaders and community pulmonologists. As a result of these strong data, we were able to raise approximately $100 million in June, giving us cash runway into 2028 and an ability to execute on the next clinical studies for each indication. It is an exciting place to be in our development, and we have not wasted any time in moving forward. Let me provide a brief update on what the team has been up to in each of our chronic cough indications. We have recently completed a couple of important Phase I studies to advance our IPF cough program. The FDA requested we conduct a drug-drug interaction study looking at any potential PK interactions when Nalbuphine ER is co-administered with pirfenidone or nintedanib, which are anti-fibrotic and the standard of care taken by patients with IPF and other progressive fibrotic diseases. We recently received the data from this study, and we are pleased that there were no clinically meaningful changes in the pharmacokinetics of any of the drug combinations used in this study. We will publish these data in the future, but we did not see anything that will impact the dosing in our Phase III program. We also made good progress on our TITLE study, which is assessing respiratory function and safety of Nalbuphine ER in IPF patients. Recall, this is a study requested by the FDA to investigate if there were any potential signs of respiratory depression in patients with IPF following dosing with Nalbuphine ER. The IPF patients in the study were housed in clinic for ten days and given increasing doses of the drug while having their oxygen, carbon dioxide levels, and respiration rate assessed for periods of time. A planned review of data by an external safety review committee in a sentinel cohort of patients concluded that there were no safety signals in the study to date. As a result, the committee gave approval to complete enrollment for the study. We will include the available data for both the DDI and respiratory safety studies in the end of Phase II meeting package. As for the end of Phase II meeting, we expect to request that meeting in the fourth quarter of this year. The key points we are looking to discuss with the FDA are to gain alignment on the Phase III program for chronic cough in patients with IPF, get their input on the Phase III study design and other parameters, as well as agree upon any other NDA enabling work which needs to be completed. In parallel, the clinical team has been preparing to initiate the Phase III program in the first half of next year and is busy lining up key vendors and identifying sites for these global studies. We have also been preparing for a study in other non-IPF interstitial lung diseases, or ILD. This population will include non-IPF ILD patients that have lung fibrosis and chronic cough. We estimate there are approximately 228,000 of these patients, with 50% to 60% having uncontrolled cough. This more than doubles the market opportunity of IPF chronic cough, and these patients are primarily seen by the same pulmonologists as IPF patients. This keeps our clinical and commercial efforts efficient and creates synergies. We plan to request a meeting with the FDA once we align on the IPF pivotal program to discuss our study design and protocol for this indication as well. Once we have FDA input, we will be prepared to initiate this study. Finally, we have been working on the next study in refractory chronic cough. We expect that study to be a Phase 2b parallel arm dose-ranging study and are planning to initiate that study in the first half of next year. We are drafting the protocol and identifying sites for this study as well. So as you can see, there's a lot of planning going on at Trevi Therapeutics, Inc., as well as preparation work to align with the regulatory authorities and initiate multiple trials in the first half of next year. This takes time to ensure that we get these trials right. We will provide updates on next steps as we gain alignment and have line of sight to study starts. I will now provide a quick review of the financial results for the quarter. The full financial results for the three months ended September 30, 2025, can be found in our press release issued ahead of this call and our 10-Q, which was filed with the SEC today after the market closed. For the third quarter of 2025, we reported a net loss of $11.8 million compared to a net loss of $13.2 million in the same quarter in 2024. R&D expenses decreased to $10.1 million during the third quarter of 2025 from $11.2 million in the same quarter last year. The reduction was primarily due to decreased clinical trial work in which those trials were actively enrolling in the prior year and reported data in the first half of this year. This was partially offset by increased costs related to our recently completed Phase I studies and personnel and related expenses.

The increased professional fees were primarily due to increased costs as we continue to prepare for compliance with SOC 404 regulations. As of September 30, 2025, our cash and investments totaled approximately $195 million. Our cash and investments give us cash runway into 2028, subject to finalizing the development for each of our indications. We expect to be able to fund two Phase III trials of Hiduveo for the treatment of chronic cough in patients with IPF, along with a long-term extension for those trials. Our planned Phase 2b/3 trial in chronic cough in patients with non-IPF ILD, our next trial in patients with RCC, and our ongoing Phase I supportive studies. So in closing, Trevi Therapeutics, Inc. is positioned with strong data in two serious chronic cough conditions and is preparing to advance into the next stage of development for each of the three chronic cough indications. Chronic cough is a debilitating condition for which there are currently no FDA-approved therapies. Also, the company is financially strong with enough cash to complete the next stage of development work to potentially advance these therapies closer to the patient. We believe we are well-positioned to execute our strategy and create meaningful shareholder value over the next couple of years. This concludes my prepared remarks. Jim, Farrell, and I are now happy to answer your questions. I will turn the call back over to the operator for Q&A.

We will now begin the question and answer session. The first question comes from Ryan Deschner with Raymond James. Please go ahead.

Hi, thank you very much for the question. Have you narrowed down more of what inclusion and exclusion criteria you would target for the non-IPF ILD study, maybe in terms of what constitutes chronic cough in those studies? And would you exclude any ILDs from an initial study in this space off the bat? Thank you.

Hi Ryan, this is Jim. So thanks for the question. We had some good discussions with our KOLs for the non-IPF ILD study. I think you can imagine that there's going to be a lot of similarity in the underlying lung disease. We'll define that in a certain way. Chronic cough, I think we're going to go in with the standard criteria. Typically, we look at some minimum amount of cough in terms of maybe 10 coughs per hour. So it'll be very consistent with what we're looking at in the rest of our program. So I think those are narrowing down rather nicely. I think the important point to remember about that type of trial is that while there are going to be patients with lots of other comorbid conditions, we're really focusing on the entry criteria being related to the amount of cough that they have and the amount of lung damage, lung fibrosis that they have. So those are going to be the defining features for the inclusion. And then there'll be other things to manage around their comorbid conditions.

And Jim, anything we're carving out?

At this point in time, we're not really carving out anything. We're going to base it on those basic criteria. So of course, it's a broad swath of conditions. And as we get closer to that, inclusion or it's closer to defining that protocol a little bit more in-depth, we may carve out one or two, but for the most part, it's going to be based on lung disease and the amount of cough.

Excellent. Very much. Maybe quickly just on the DDI study, would you anticipate needing to do any more studies like that for a trial like this or subsequent trials? Outside of, I guess, chronic cough and RCC.

Yeah, so that's great, Ryan, thanks. So the study we got done was a DDI looking at our drug with pirfenidone and nintedanib as the key antifibrotics in this space. There will be other DDI studies that we will have to do based on the mechanism of drug metabolism. We are metabolized by CYP, primarily the 2C9, 2C19 species. So there will be a DDI looking at probably a 2C9 inhibitor. These are things that we'll talk with the FDA about, but it is expected that we will have to do a couple more Phase I studies and at least one more DDI study.

Thank you very much.

And the next question comes from Annabel Samimy with Stifel. Please go ahead.

I just wanted to clarify for the respiratory study, you had interim results from the DSMB saying that you have no issues. Do you need to complete that study before you have the end of Phase II meeting with the FDA? And is there any other hurdle that you need to get past for that meeting? And then separately, if you could just share a little bit of the feedback that you've been hearing from the CHEST meeting at this point, how are the pulmonologists looking at this? And how do you start thinking about targeting the market that you're looking at? Thanks.

Hi, Annabel. So on TITLE, we had a sentinel cohort of four subjects that we completed. And the plan was to have our data monitoring committee review those subjects. That all went fine. There were no safety issues identified. So we continued on. To answer your question, we will have the available data when we submit the package.

Really hasn't been a lot of work done on things that matter day to day to the patient. So we're getting a lot of attention in our sessions. The data has gotten a lot of attention. And we also hosted a reception one night that was very well attended by U.S. investigators interested in getting into our study. So, really encouraging. Jim and I were both there and quite busy the whole time. I think, Sarah, I'll let you take on sort of based on the feedback how you might be thinking about targeting the market with any feedback.

Yes. Thanks, Annabel, for the question. When we look at the market, we do need to raise the burden of disease, and that's work that's ongoing. That we're continuing and we'll launch next year. There's also just targeting in terms of how we look at segmenting this market, which will start next year just to make sure that we have appropriately sized our field force to target the key prescribers in this area. So that's some of the work, and then we're continuing to always do physician and payer research to understand how our new target product profile based on the positive core results is seen by physicians and payers within this space.

Great, thank you.

And the next question comes from Leland Gershell with Oppenheimer. Please go ahead.

Great. Thanks for the update and taking the questions. Just a couple, joined a little bit late, so my apologies if you may have covered. But as you head into the end of Phase II meeting, Jennifer, are there any particular questions or issues that you would like to address for your clarity on? Then also wanted to ask on the drug-drug interaction side, is there any need for Trevi to run interaction studies within patients who may be on other opioids concomitantly? Thank you.

Leland, this is Jim. So in terms of the end of Phase II meeting, standard questions are going to be related to the protocol design, endpoints, duration of the study, really nuts and bolts around the Phase III. We'll be submitting a full final draft protocol to them, so we'll have the protocol with them in hand. And we will guide some of the more important questions regarding the design, patient inclusion, exclusion criteria, our statistical approach, pretty basic things that are really important to narrow down at this meeting. So we will have absolute clarity on what we need to do for the Phase III coming out of that meeting.

Safety database size too is an important one.

Safety database size, we will be discussing the extent of any long-term data collection. And we'll also be, as we've talked about the DDI study, we did talk that we may need to do some more work in the Phase I world on wrapping up things for the NDA submission. We will probably do another drug-drug interaction study that encompasses our mechanism of drug 2C19 in particular. So we'll be asked to do a drug-drug interaction study with drugs that are inhibitors of that system to understand what the effects are on pharmacokinetics. There might be some other Phase I studies that we're anticipating that we will discuss with the FDA at the end of Phase II meeting as well.

I would add though, Leland, I think you specifically asked about other opioids. They are contraindicated. We have excluded them because as you know, our mechanism is a mu antagonist. So if you're on other opioids, it will put you into opioid withdrawal, which is obviously super helpful from the addiction side and labeling side. But we do contraindicate that in our trials and it will be in our label.

Yes. Thank you, Leland.

And the next question comes from Judah Farmer with Morgan Stanley. Please go ahead.

Yes. Hi, guys. Thanks for taking the questions. Maybe could you help us with the latest thinking on the potential to incorporate the non-IPF ILDs into the Phase III program for IPF. Will you get any clarity on that at the end of Phase II, do you think, or do you have to wait for that subsequent interaction? And then what are your thoughts on launching with both indications in the same label versus sNDA? And then secondarily, obviously, high level, but any thoughts on changes in CBER leadership and impacts of the programs? Thanks.

I'm just going to comment on strategy. We could probably both do this. But I think, Judah, we made a decision that we're going to go in with sort of our strongest foot forward and do the end of Phase II meeting. Jim's got a lot of data, robust data. We want the FDA to catch up with where we are, all the studies we've run, the data we've generated. And we will tease up there that our broader program includes both RCC, but importantly non-IPF ILD, which we think shares a common biology. So we will tee that up, but you only get one hour in this meeting, and we don't want to get distracted debating non-IP ILD there because to Jim's point, we need to walk out with clear guidance on our Phase III program. So really trying to protect that and keep it whole. As soon as we feel we have alignment with the agency, we're going to be prepared to submit a protocol and non-IPF ILD and request a Type C meeting. Hopefully, that's a pretty easy ask coming off the heels of the IPF end of Phase II. So that was sort of a strategy point because we could have jumped in earlier, but felt we wanted our strongest foot forward. I mean, as far as the sort of CBER change in leadership, and I'll let Jim add any color as well. I mean, obviously, a new person named this week, an oncology person, I don't know how much that's really affecting the divisions we've had. I mean, baffling to me, timely feedback, on time, clear communications. I don't know how the FDA is holding it together. Kudos to them. So I don't know how much those levels are affecting things. When you're in a clinical trial mode. I'm sure at the point in time they look at your NDA it does. But hasn't seemed to impact what we're doing. I don't know, do you have anything to add?

No, nothing to add to that other than I think the surprise factor of how responsive they've been is has been high on my list. It's like this is very unusual for me to get this kind of responsiveness. So very pleased about that.

Great. Thank you, Judah.

And the next question comes from Serge Belanger with Needham and Company. Please go ahead.

Hi, good afternoon. I think in the past you've discussed the potential of HYDUVIO being eligible for orphan drug exclusivity in IPF cough. Just curious if you have any updated thoughts on that and whether that's something you will seek like an orphan drug designation in the upcoming end of Phase II meeting with FDA? Thanks.

Jim's laughing because he made me promise. We are going to request orphan drug for IPF. I do always warn people that, you know, I don't want people to put too much in that. Although IPF has gotten orphan drug. This is cough in IPF and cough is a broad problem. So we'll see what they have to say. So we will apply, I think it's an answer we should know. Jim made me promise that we wouldn't do that until after we went through our end of Phase II meeting. He doesn't want them to be distracted on any other side questions. So I think on the heels of end of Phase II, we'll go ahead and submit for that and find out their views on cough and IPF.

Thank you.

And the next question comes from Rowena Ruiz with Leerink Partners. Please go ahead.

Great. Good afternoon, everyone. So a couple for me. First one is given the evolving IPF landscape with recent positive data from United Therapeutics TETON study, I was curious how could that impact how Haduvia fits into the prescribing approach and treatment algorithm of physicians? Michelle, you want to take that or I can as well?

Yeah, happy to. Thanks, Rowena, for the question. If anything, it probably doesn't really change much for us. When you think about chronic cough, the high burden of disease among these patients, physicians look at this as either first or second line therapy, and that can be before an anti-fibrotic or after an anti-fibrotic is initiated. When you look at the drugs and the new approvals that are already coming to market, they're still slowing the progression of the disease and they're not having a positive impact on the cough. So there's still a very high place for a chronic cough therapy and concomitant therapy with these anti-fibrotic products that are on the market or potentially coming to market.

And so I would just add too, I've heard a lot of discussion about, you know, with improvements in therapies and treatments for patients, it probably just improves the diagnosis. So the patient groups will start to grow, I think people are focused on this disease a little more. Hopefully, cough comes to the forefront when we actually have something for treatment. So it's obviously great for the patient to have options. But I just think overall, it probably grows the market as well.

Yep. Makes sense. And a quick follow-up about the TITLE study. What do you hope to see in the results in terms of a best-case scenario now that you can complete enrollment? And any sort of thoughts on how that might impact the end of Phase II discussion with the FDA?

Yes. Hi, this is Jim. So we are looking at basic respiratory function, PO2, CO2, and respiration rate. FDA was interested in a study like this just to make sure that we don't have any blatant signals regarding respiratory depression. So we're taking a very fundamental approach on key respiratory parameters and looking at those. The ideal outcome for this study and the data have been great so far is that there's no findings here. There would be no findings, meaning that there's no changes on any of those parameters. We are dosing at night, looking at these IPF subjects while they are asleep, which is considered a conservative way, the most sensitive approach to this. So that's the nature of the study to really pull out if there's anything there. So obviously clean results and no impact on the program is the ideal outcome. Ideal here.

Jim, I would just add. We've obviously had this in what two hundred people now, IPF patients clinically. And never seen any signal. So I think this will just sort of go hand in hand with the safety database they look at as well.

Makes sense. Thanks.

Thanks, Rowena.

And the next question comes from William Wood with B. Riley Securities. Please go ahead.

Hi, thanks for taking our questions today. So a couple from us, kind of focused on the Phase III. It sounds like from what I can tell you, you've essentially got your sort of Phase III package sort of put together in terms of how you want it. Obviously, that's got to be discussed with the FDA and approved or at least agreed upon. But I was just curious if you could walk through sort of maybe what you're thinking at a high level in terms of doses and or timing titration you're looking to take forward? And maybe just remind us are you going to allow patients to use background anti-fibrotic in the study? And will you be looking at a biomarker improvement within the study? And then lastly, just briefly, would this be conducted in the same sites that your other Phase IIs were, or will you be branching out further?

Sure. I think I can remember all those. I got them written. I got them down. So William, thanks. This is Jim. So in terms of doses, we did CORAL was a great study for us because we learned a lot from it, including that was our definitive dose-ranging study. So in terms of dose going forward, we did a lot of work over the summer. We interrogated the fifty-four and the one hundred eight-milligram dose group in CORAL because of the titration up, we were able to determine in individual subjects and looking at dosing groups. At the one hundred eight, really didn't add any significant value to the fifty-four milligram BID dose. So fifty-four milligram BID will be our top dose going forward. Twenty-seven milligram BID dose is a titration dose. We identified that as a minimum effective dose in the CORAL study. So it will not be considered a treatment dose, but it will be considered a titration dose. What we also learned from the CORAL study is that when we do our titration, as we've done in all of our programs to date, we see that most of the adverse events that we see typical for this compound, which are mostly GI and CNS in nature, most of those come on with the initiation of dosing. So what we're going to do is extend a little bit further the once a night dosing under the twenty-seven milligram dose, go into twenty-seven milligrams BID, and then get our fifty-four milligram BID treatment dose. So we will extend that titration period a little bit. To mitigate some of the earlier side effects that we see with the compound. And just a reminder about the adverse events that we see with Nalbuphine. Is that we typically see some GI and some CNS. These are typically transient and these are typically things that do tolerate out over time. And that's why we're going to extend that titration period. In regards to your question about allowing background antifibrotics, over eighty percent of our subjects in the CORAL study were on either nintedanib or pirfenidone. So yes, we are going to allow approved anti-fibrotic as background medication. In terms of biomarkers, we don't have any intention of looking at those in any, well, we're not going to look at those. And in terms of the sites, if you recall in CORAL, we were running that study ex-U.S. We will be going back to the more successful sites in that region. And we will also be bringing in a large number of U.S. centers. The great thing about the Pulmonary Fibrosis Foundation is that there are over 80 excellent care centers. And we are talking to them about conducting our trial. So we will be bringing in, in a major way, U.S. centers as well as Canada and Europe.

Got it. That's very helpful. Thank you for answering all my questions. Very briefly and lastly, the end of Phase II package, once you actually get that submitted and discussed, will you be relaying that to us and or investors, the public? Or is that just how will that be dispersed, I guess?

Yeah. No, it's a good question, William. I think typically you do the meeting and then you wait thirty days for the minutes. Usually, you want to wait to see the minutes so that what we think we heard we actually see in writing when we get it. When we have that information, we'll definitely give an update to the Street. I mean, we probably won't put out a separate press release. I think one of our earnings calls or some venue, we'll use it to update people. But yeah, it's important information for sure.

Got it. Helpful. Thank you very much, and I'll hop back in the queue.

Okay. Thanks, William.

The next question comes from Kaveri Pohlman with Clear Street. Please go ahead.

Hi. Good evening. Thanks for taking my questions. So my first question is about how well do the current trial match the real-world patients, things like, you know, the inclusion exclusion criteria? Comorbidities, or, you know, use of other drugs. And for future trials, for both IPF and RCC, do you plan to make the eligibility criteria broader to include a more diverse population, or will they stay the same?

Yeah, hi, this is Jim. So we will keep this population for the Phase III as broad as possible. We are really trying not to make it strictly a clinical trial population, but we want to keep it broad. So we are working with the KOLs to really refine our inclusion and exclusion criteria to make it definitely more real-world. So we will have few restrictions other than they need to be diagnosed with IPF, they need to have some other things that make them relatively healthy that they can actually be involved in the study. So I can promise you that it will be as broad as possible, as real life as possible.

Not too much different than our 2b, right?

Not very much different, in fact, somewhere else. Actually refining a few things to broaden it from our 2b. We will allow basically unless something that is going to interfere with our ability to measure cough or will have a direct impact on cough in the trial. Their concomitant medications will be allowed per normal. And I don't know if there's any, what else did you, was there anything else that you asked?

I think I covered those two things. Okay. Right. Yeah. That's helpful. And, I also want to understand for the RCC Phase 2b trial, do you plan to study the same dose regimen as it was in the Phase 2a or do you plan to kind of test QD options also since the drug seems pretty safe?

Yeah. We're actually going to probably eliminate the top one hundred eight dose in that trial. And we will be exploring QD dosing, once a day dosing in that trial as well.

As well as BID.

As well as the BID. So we'll probably add a 27 QD arm in there, because if you recall, the data, our twenty-seven BID dose was about as effective as the two higher doses.

Got it. And maybe just like a last one. Respiratory safety study, it was surprising that the FDA needed that after you showed 200 patients worth of data. But I still want to understand, will you be assessing long-term effects? Do you need to keep patients on to provide that data or it's not required?

So I think the FDA is curious about doing a very specific study. I've been in this situation before where they like to see a more directed controlled study just rather than collecting adverse events. So I think it's their progress to ask for a study like this, I think it's going well. I'm sorry, what was the second part of it? Long term. I mean long term or long We will do long-term data collection in our Phase III program. The anticipation based on previous FDA experience here is they'll be looking for something like fifty-two weeks of safety data.

Got it. Alright. Thank you.

Thanks, Kaveri.

I'm not showing any further questions. This concludes our question and answer session. I would like to turn the call back over to Jennifer Good for closing remarks.

Thank you. We appreciate you joining us for today's call. I know this is the end of earnings season, so you're all probably happy as well. Enjoy the upcoming holidays and we are available after the call or tomorrow for any follow-up questions that you may have. Thank you.