Good afternoon, and welcome to the Trevi Therapeutics Second Quarter 2025 Earnings Conference Call. 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 these 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-Q, 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, even 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 second quarter 2025 earnings call and business update. Joining me today on this call are my colleagues, Lisa Delfini, Trevi's Chief Financial Officer; Dr. James Cassella, our Chief Development Officer; and Farrell Simon, our Chief Commercial Officer. Lisa and I will make some comments on the business and financial results, then the team is happy to answer any questions that you may have. The first half of this year has been a major inflection point for Trevi, 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. As a result of this strong data, we were able to raise approximately $115 million in capital for total cash and investments at the end of June of approximately $204 million. This gives us strong runway to execute against several important clinical milestones in each of our programs. It is an exciting place to be in our journey, and we believe we are well-positioned to execute our strategy and create value. Let me provide a brief update on what we have been up to this summer. As you all know, the top line results from our CORAL trial were announced in early June with Haduvio meeting the primary endpoint with a statistically significant reduction in 24-hour cough frequency across all dose groups studied. Since reporting our top line data, we have received the full data set from the trial and can confirm that the data across the secondary endpoints were consistent with the top line results. Importantly, the quality of life assessment in our patients using the Leicester Cough Questionnaire, or LCQ, showed marked improvement with a statistically significant reduction at both the 54 and 108-milligram BID doses. The LCQ is a 21-point scale with 3 different domains: physical, social and psychological; an increase in total score of 1.3 points is considered clinically meaningful. For the 54-milligram and 108-milligram BID doses, there was a statistically significant 3.7 and 3.4 point increase, respectively, p equal 0.01 for the total LCQ score at week 6. These are strong results for a 6-week study. The LCQ is meaningful in patients with IPF. In fact, the publication from the large U.S. Pulmonary Fibrosis Foundation Registry demonstrated that a worse quality of life as measured by the LCQ correlated with the risk of worse health outcomes such as respiratory hospitalizations and mortality. One of our key focuses at Trevi is remaining patient-centric as we plan for development and commercialization. In a recent patient advisory board meeting, we reviewed the CORAL results to get patients' reactions. The 2 most important factors to patients when looking for a future cough treatment are seeing improvements in cough frequency and severity and quality of life, similar to what we've heard from physicians. Several patients remarked that with the kind of change in cough seen in CORAL, it would be incredibly impactful and positive in their day-to-day lives. I was struck by how much cough controls patients' daily activities and how they isolate or compensate to avoid the embarrassment of coughing out in public. Coming off this data, Jim and his team have been very busy preparing for the end of Phase II FDA meeting and the next set of trials. We will provide more detailed guidance when we initiate each trial. But let me give you a brief update on the priorities over the next few months. First, we are currently conducting a couple of important Phase I studies. We are working on completing our TIDAL study, which is studying the respiratory function and safety of Haduvio on IPF patients as well as conducting a drug-drug interaction study looking at any potential PK effects of nalbuphine when co-administered with pirfenidone and nintedanib, both antifibrotics that are taken by patients with IPF, and other progressive fibrotic diseases. We expect to have the data from both of these trials in time for our end of Phase II meeting with the FDA. 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 cough and IPF, as well as any other NDA-enabling work which needs to be completed. In parallel, the team has been preparing to initiate the Phase III program in the first half of next year. We have also been preparing for a study in other non-IPF interstitial lung diseases. This population will include non-IPF patients that have lung fibrosis and 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 cough, and these patients are primarily seen by the same pulmonologists that see the IPF patients. This keeps our clinical and commercial efforts efficient and creates synergies. We plan to request a meeting with the FDA this year to discuss our study design for non-IPF-ILD and the protocol for this indication. 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 to be a Phase IIb parallel arm study design, looking at dose-ranging and are planning to initiate that study in the first half of next year as well. So, as you can see, there is a lot of clinical development planning going on at Trevi as well as preparation work to align with the regulatory authorities. This takes time to ensure that we get this next set of trials right. We will provide updates on next steps as we gain alignment and have line of sight to study starts. I will now turn it over to Lisa to review our financial results, then we will open it up for any questions you may have.

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the 3 months ended June 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 second quarter of 2025, we reported a net loss of $12.3 million compared to a net loss of $12.4 million for the same quarter in 2024. R&D expenses decreased to $9.4 million during the second quarter of 2025 compared to $10 million in the same quarter in 2024. The reduction was primarily due to decreased costs related to our Phase IIa RIVER trial, our Human Abuse Potential study, and our Phase IIb CORAL trial, all of which were actively enrolling in the prior year. This was partially offset by increased costs related to our recently initiated Phase I drug-drug interaction study and personnel and related expenses. G&A expenses increased to $4.3 million during the second quarter of 2025 compared to $3.3 million in the same quarter of 2024, primarily due to an increase in professional fees and personnel and related expenses. The personnel and related expenses were primarily due to increased headcount. Approximately $500,000 of the $1 million increase in total general and administrative expenses was due to costs to prepare for SOX Section 404(b) related to our internal controls. These requirements become more rigorous as the company's market cap grows. As we continue our readiness efforts, we expect approximately this level of expense for the second half of 2025 and the expense may increase going forward. As of June 30, 2025, our cash and investments totaled approximately $204 million. As Jennifer mentioned, the increase in our cash and investments was primarily a result of the successful public offering we completed in June 2025 after the release of the data from our Phase IIb CORAL trial that resulted in gross proceeds of approximately $115 million, including the full exercise of the greenshoe. Our cash and investment balance gives us cash runway into 2029 and enables us to fund 2 Phase III trials of Haduvio for the treatment of chronic cough in patients with IPF, our planned trial for chronic cough in patients with non-IPF-ILD, our next trial in patients with RCC, the Phase I work Jennifer discussed, and it enables pre-commercial planning activities. In summary, Trevi is in a strong position financially to execute our business plan. This concludes our prepared remarks. I will now turn the call back over to the operator for Q&A.

The first question comes from Faisal Khurshid from Leerink Partners.

It kind of feels like a calm after the storm moment here. I wanted to ask on the respiratory depression study. Could you comment a little bit on the progress of this study and just what it entails in the logistics? And what I'm trying to get at is like for investors, should we think about this as just sort of like any risk involved in that study? Or how to kind of like think about the outcomes there?

Faisal, Jim here. Thanks for the question. So, our respiratory safety study, as you know, is about looking at the potential effects of nalbuphine of Haduvio on respiration, looking at rate, CO2, and O2 in patients with IPF. So, it is an assessment study. It's to characterize if there's any effects there in this patient population. I would say that it is an informative study. It's a study that the FDA has been looking for in order to understand the characteristics in those patient populations. So, the progress is that we have the study ongoing. We have 2 active sites. We did do some tweaking when I arrived at the company. We modified the protocol to make it simpler and easier and a little bit more straightforward. So, there was a little bit of a delay in sort of the changes that occurred there. But we are on track, and our expectation is still that we will have data for the end of Phase II meeting.

Got it. And then just on the DDI study, could you just comment on why that's a requirement considering that you had background antifibrotic use in your prior IPF studies?

Yes, that's a great question. This Phase I study is designed to characterize potential metabolic drug interactions. Our drug is mainly metabolized by CYP liver enzymes. Patients will be treated with antifibrotics like pirfenidone and nintedanib. This study serves to confirm the metabolic pathways of those drugs. No significant drug-drug interactions are anticipated. However, these studies are important before advancing to Phase III to determine if combining these medications alters the pharmacokinetics of either our drug or the others, which could affect overall efficacy. We are aware that some data from Phase III indicated pharmacokinetic interactions that did impact efficacy for at least one dosage. Since patients with IPF will be taking these drugs, this study was planned as it aligns with FDA expectations.

The next question comes from Jason Dorr of Oppenheimer.

Jason here standing in for Leland Gershell. One or 2 questions from us, first of which is going to be, how are you thinking about the key questions to iron out in the upcoming FDA meeting as your team plans for Haduvio's Phase III trial in IPF cough? And regarding one of your other indications, what color can you provide on the soon-to-start trial in non-IPF ILD chronic cough?

Jim, you're the guy. Go ahead.

Happy to talk about both of those things. So, end of Phase II meeting is a very important meeting. It's also a very routine meeting for anybody that's going to advance clinical development. The key thing that we'll be bringing to the FDA at the end of Phase II meeting is the data we've collected to date, especially data from CORAL, which was our definitive dose-ranging study. It's about the adequacy of where we are in our program, how we establish the doses that we want to use and primarily to talk about the Phase III program, the readiness to be into Phase III, the specifics of the protocol. Typically, the protocol for the Phase III is submitted as part of the briefing document. So, we'll definitely have a lot of discussion about the Phase III, get their buy-in on that, as well as, as we look forward towards NDA, the other anticipated trials that we may or the FDA may decide that we need to do in order to have a sufficient package for registration purposes. So, things like these DDI studies that we're doing will all be part of that package. So, we'll have that conversation with the FDA then as well. And one of the other things that's important to get out of the end of Phase II meeting is what the expectation is on the size of the safety database, the duration of the data that is included in the safety database. And as we've been expecting all along and talking about some kind of a long-term extension trial beyond our Phase III that will satisfy the FDA's requirements for longer-term exposure than what we need to do to show the preliminary safety and efficacy. So that answers that part of the question. I'll pause there if you have any other questions on that. On the non-IPF-ILD, we've had a lot of great interactions with pulmonologists and KOLs in this space. As you know, IPF is an interstitial lung disease. It's a very well-defined population. As you heard from us before, there are a lot of other patient groups who have interstitial lung disease, but not IPF. So, people with rheumatoid arthritis or Sjogren's or systemic sclerosis. So, we'll be looking at that other population defined by a certain amount of lung fibrosis as well as minimum cough. So, we'll be really looking at that part of the population. We expect the endpoints and everything will be the same as in the IPF because it is a continuum with the IPF population, with the underlying lung fibrosis. So, I think we have a pretty good handle based on our conversations with the experts here on what we need to do for the conduct of that study. So, it really is expanding the patient base.

I would just add that I previously referred to this next study as being a Phase IIa crossover. However, after reviewing all the IPF data and consulting with the key opinion leaders, it's clear that this drug effectively addresses cough. Initially, there were doubts about the value of proving this concept, but we have adjusted our approach to consider a parallel arm design, which could expedite the program. Our goal is to align with the regulatory agency on this strategy and find a way to integrate it with our IPF program as we progress. Overall, this reflects a slight shift in our perspective as we've gathered more data.

The next question comes from Annabel Samimy of Stifel.

I would like to follow up on the previous point about the parallel design for the non-IPF-ILD study. I recall some key opinion leaders mentioning that ILD patients or non-IPF patients exhibit similar disease progression and have a common fibrotic mechanism or interstitial lung disease mechanism related to their cough. When you mention a parallel design, could this potentially resemble a basket trial? Would it be sufficient to remain in Phase II without needing to quickly transition to Phase III for label expansion? Is the goal to demonstrate some level of efficacy given that this mechanism appears to be broadly applicable across various cough indications? That's my first complex question.

Question of the day. We've been debating that in here. Go ahead, Jim.

Annabel, yes, the answer is yes. So yes, I would characterize it less as a basket trial and more as there's going to be a minimum criteria for coming in that will allow these patients that may have very different kinds of comorbidities to be enrolled in the trial. So, your point is that there is a commonality here on the fibrosis and in some cases, even the progression. So, we'll be maybe a little bit more opened up and less specific on certain types of comorbid conditions coming in. So that's on the basic pool. So again, I think we've gotten broader in our thinking in that regard with the help of the experts who feel like this is like the fibrosis is really the key criteria here.

And cough.

And the cough. And obviously, the cough. So, the parallel group or parallel arm design study, think of what we learned from CORAL. And as Jen said, it's really good to jump to something like that now. We don't really need to do the proof of concept. I think we all are believers there. I think the key is that we will be able to look at this initial Phase II type study digest the results and as appropriate and with further conversations with FDA, maybe even meld it into our IPF program as we move things in parallel down the road. I think the important point here is that things will be moving in parallel. And when there's opportunity and the right kind of data sets, we will be able to have those discussions on melding.

Next question comes from Josh Schimmer of Cantor Fitzgerald.

This is Alexa Deemer on for Josh Schimmer, and congrats on a great quarter. So, my question is with more of the complete data for CORAL now available, how are you thinking about which dose or doses to bring forward in the Phase III study?

Great question. So, we know that when we look at our overall data sets, the 54-milligram BID dose is really a sweet spot dose. It really performed quite well. It really had broad impact across our primary and secondary endpoints. So, we know that as we think about this, the 54-milligram BID dose is going to be a key dose that we bring forward. Obviously, there will be a placebo control. We will be discussing with the FDA our dose selection rationale. So, we can't really talk about all the specifics there. But I think you can anticipate that 54 is going to be a key dose bringing forward.

The next question comes from Serge Belanger of Needham & Company.

I believe you mentioned the complete results of the CORAL trial that you received in the last month. Can you provide more context about the LCQ data and how it relates to the primary endpoint? Also, are there other secondary endpoints we can expect to see at medical meetings or in future publications?

Sure. So, the Leicester Cough Questionnaire is a really widely used quality life questionnaire. We reported previously that we have very significant findings at the total assessment. When we look at the domain scores of physical, psychological and social domains, especially like I mentioned the 54 dose, we see very, very strong effects on those domains. So, these are looking at the impact of the cough on their physical domain, social aspects of their life, psychological aspects of their life, and we see very clear significant findings, again, focusing on the 54 dose, very, very clear findings there. So I think that really helps. It complements the objective cough data that we have. So, this is objective cough is measured with an instrument. This is now the patient opining on how their life has been changed, their quality of life on these specific domains and rolling up into this total score. So, I think it complements and puts the patient perspective in the light of the reduction in cough frequency. So, that's a very, very important assessment tool, and I think a very important one when we look at quality of life. We have looked at the other patient-reported outcome measures that we'll talk about at future meetings, patient global impressions, clinician global impressions, and we talked about the cough severity scores. So, there will be lots of secondary endpoint patient-reported outcome data to come at further meetings.

I just wanted to add something to what Jim was saying. The LCQ is a really important thing in terms of reimbursement and value, painting that overall picture in addition to the primary endpoint and the key secondary endpoints. So I think Jennifer said upfront, the linkage also here is if you look at the U.S. Pulmonary Fibrosis Foundation Registry, there was a strong link and correlation between baseline LCQ and impact on health outcomes. Now that will be seen over a much longer period of time. And I think that's something that we'll look at as we go to a pivotal program. How does this impact things like respiratory hospitalization and mortality.

And maybe a non-Jim question for Lisa. Should we expect OpEx to remain relatively flat from 2Q levels? For the remainder of the year until some of these larger trials get underway in 2026?

Yes, that's right, Serge.

The next question comes from Deb Chatterjee of JonesTrading.

So I had one question on RCC. So based on GSK's latest guidance, it seems that the KALM-2 will now read out potentially the second half of 2026 with KALM-1 data coming together as a bundle. So, I was just curious, are you aware of any particular enrollment criteria related, maybe delays? What is actually the headwind for the trial? And are there any implications for the RCC trial you're planning? And I have a quick follow-up.

So this is Farrell. I can talk about just what we know. I mean we don't really comment on competitive reasons. We don't have any insight into what's causing some of those delays. What we know is when we look at our opportunity within RCC, we have the potential to be best-in-class in that indication. And I think that's the difference in approach that we're taking of going after a treatment-resistant population, those who failed other therapies. There's still a large patient opportunity there.

Yes. And I would just add, we would have loved to have seen their data before we fired off on our trial, but we're not going to hold up and wait for it. So, I think at this point, with their data sort of slipping back, we're going to be ready to go before that. So, it's going to have no impact on our program.

No impact at all. And I think the strength of the data that we had from the RIVER trial, I think will have really positive impact on our ability to run the next trial as well. I think that that's also a thing that that not only physicians but the patients pay attention to as well. So, I don't anticipate any problem. I don't know what the delays are related to there. I know they're running a big global trial, but our next trial is going to be dose ranging coming off of really solid data. That will go a long way.

Very helpful. And a quick follow-up. This is like related to IPF. So, you mentioned the drug-drug interactions with nintedanib and pirfenidone. Any plans of checking for drug-like interactions with nerandomilast?

No. There will be some other drug-drug interaction studies that, again, relate to mechanism of metabolism. Those are very standard. They've been on our list of things to do before the NDA. But no, I think those are the 2 antifibrotics that we'll be focused on.

Next question comes from Ryan Deschner of Raymond James.

Have there been any other interesting trends or post-hoc analyses coming from CORAL RIVER that have caused your perspective on dosing to evolve in either indication? And can you also give us any additional detail on what specifically you're planning to present at ERS later this year?

We've done a very deep dive on analysis of our dose effects. We've absolutely I think, concluded that 54 is a very key dose for us. I don't want to get ahead of our skis on talking about how we might approach another dose in the trial until we have that conversation with the FDA. But I think you can really see based on the analysis that we've done internally and had discussions with some experts and statisticians that 54 is going to be an anchor dose for us.

Yes. And otherwise, Jim, I would just add, no surprises, right? AEs came on early. They tend to dissipate quickly. I mean it's the same personality that we've seen in every sort of trial.

And obviously, 27 will be used at a minimum as a titration dose.

Yes, I think just robust. As far as your question, Ryan, on presenting at ERS, we have 2 abstracts that have been accepted on RCC. We're going to be putting our IPF data in at CHEST because we wanted that presented in the U.S., which is in October in Chicago. So those are the 2 medical meetings that our data will be hopefully presented at. We know we've been accepted at ERS for RCC, but we don't know about CHEST yet.

Excellent. Congrats on the progress.

The next question comes from Brandon Folkes of H.C. Wainwright.

Maybe just coming back to a bit of an old topic here. But understanding there's not really a commercial impact on the scheduling in the IPF patient population. Have you done any commercial work or have any thoughts on scheduling impact in the non-IPF ILD indications just in terms of prescribing habit?

Thanks, Brandon. This is Farrell. So, we've done some qualitative work within that space to talk to providers. When you look at the overall key prescriber in that area, it's still going to be that pulmonologist. And so it really is the call point to the pulmonologists where we don't see a sensitivity to the mechanism behind the prescribing. We're going back and testing an updated TPP based on the CORAL results. We'll test that across a broad range of potential patient types, but we don't anticipate an impact in non-IPF-ILD either.

Great. And maybe just one follow-up. Understanding what the respiratory depression study is about here. But if we see any anomalies unexpected on the negative side, is there any obligation in terms of submitting that to the DEA in terms of scheduling? Is there any precedent that we need to keep one eye on sort of the outlier event if we do see something in that data on scheduling? Or is that completely closed now?

I don't think that the respiratory safety study will have any direct impact on scheduling per se. I think it really is about just establishing and showing the characteristics that we're looking at in that study. I think scheduling is really going to be based on abuse liability and potential on that side.

The next question comes from Kaveri Pohlman of Clear Street.

As we enter the Phase III trials, which will have a longer follow-up compared to Phase II, how do you plan to address the placebo effect? What challenges from Phase II have you overcome that give you confidence for the next phase? Based on historical data and your experience, are there any new obstacles you expect in Phase III? Additionally, as you prepare for Phase III, could you clarify if there are any additional manufacturing steps needed for potential commercialization? What are your current thoughts on partnering for commercialization?

I can take the first question. We have gained significant insights from the program so far. The CORAL study served as an important testing ground for our parallel group design. We learned a lot, particularly about the rapid onset of effect. The efficacy of the drug became evident by the two-week mark, and it largely stabilized from then on. We don't expect any changes beyond this. Throughout the six-week study, we observed that the efficacy was stable from weeks two to four without any new safety concerns arising during the later dosing weeks. Therefore, we don't anticipate issues related to that. Regarding the placebo effect, we didn't really observe one; our trial was well-controlled, and even in larger trials, we should be mindful but the effect size was significant. I don't foresee challenges managing the placebo effect given our current data. As we look ahead to longer-term dosing trials, I believe we've tested our parameters thoroughly. We haven't encountered any late-emerging issues reminiscent of opioid histories, as most concerns tend to arise earlier. This was evident in our trial, especially during the titration phase when adverse events decreased significantly and did not return even at the 108 dose level. I don't expect any surprises going forward. Regarding manufacturing, we are equipped to produce and supply the drug for larger trials. Our team has experience in Europe and other regions and is familiar with distribution logistics, so I don’t foresee any issues on the Phase III front. We have an experienced team that has conducted large trials before and has operated in various locations. Overall, I do not anticipate any problems.

We do all the development work to get to the right point.

So, that's something that Farrell and I always spend time on, obviously. I think where partnering is probably most relevant for us is in Europe or Japan. In the U.S., Farrell is kind of all steam ahead on how this gets commercialized here. I think if somebody wanted to have those rights in the U.S., they'd have to buy the company. So really no change for us. We wouldn't look to probably partner this now in Europe or Japan, maybe Japan, I guess, but not Europe. We're just really focused on our Phase III program, how we get to the end, get good data and obviously are in relevant conversations with strategics as it makes sense for the company.

Congratulations.

The next question comes from Mayank Mamtani from B. Riley.

Could you please touch on the dose levels you're exploring in the 2 Phase I trials? And also, curious if this dose-finding work between IPF chronic cough and RCC helps you with the IP strategy? And just maybe my follow-up on the CHEST presentation for the IPF data, would you have any FVC data there maybe segmented by background therapy or without background therapy?

I'll address the CHEST topic, and then Jim can handle the others. The CHEST presentation will mainly feature the primary data we've already shared regarding IPF. We do not intend to publish FVC data, as it's primarily a safety measure and the study duration was too short to derive significant conclusions. I don't want to raise any expectations about new findings being released. It will focus on our primary data. Additionally, I can take the IP question. After every study, we consult with our IP lawyers to review all findings and identify any potential label claims related to dosing. This is an ongoing process, and we will need to see the data to determine if there are any unexpected insights from which we can file dosing claims.

The Phase I studies are single dose strength studies that we compare. The TIDAL study involves dose escalation up to the highest dose being used in that study. The EI study compares nalbuphine at a single dose strength against pirfenidone and nintedanib under various dosing regimens.

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

We appreciate you joining us for today's call. Enjoy the rest of the summer, and we are available after the call for any follow-up questions. Just e-mail Lisa or myself, and we will get you on the schedule. Thank you.

The conference call has now concluded. Thank you for attending today's presentation.