Good afternoon. And welcome to the Trevi Therapeutics Second Quarter 2024 Earnings Conference Call. At this time, all participants will be in a listen-only mode. After today’s presentation, there will be an opportunity to ask questions. 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 Factor 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 2024 earnings call and business update. Joining me today on this call are my colleagues Lisa Delfini, Trevi’s Chief Financial Officer; and Dr. David Clark, Trevi’s Chief Medical Officer. I will give an update on the progress in our clinical trials, and Lisa will give a brief financial update. Then the three of us are happy to answer any questions that you may have. This has been a fun but busy quarter at Trevi as we continue to execute against our clinical development plans for both chronic coughs and idiopathic pulmonary fibrosis, or IPF, as well as refractory chronic cough or RCC. We have a number of data readouts expected by year-end and are hoping to build on the strong efficacy data we saw in our Phase 2a trial in IPF chronic cough. To support this fast pace and focus on execution, we continue to bolster our team, and we’re happy to announce in April the hire of Dr. Meg Garin, who was key in progressing the clinical development of camlipixant while at Bellus Health. Meg is overseeing our RIVER trial day-to-day and has already started looking ahead to planning for our next trial. She has been a great addition to the team. Let me provide a brief update on our clinical trials, beginning with our Phase 2a RIVER trial in RCC, which is expected to read out in the fourth quarter of this year. RCC is a debilitating disease that affects approximately 2 million to 3 million U.S. adults and is defined as a persistent cough lasting greater than eight weeks, despite treatment for an underlying condition or where no underlying condition exists. With a lack of any approved therapies for RCC in the U.S. and several drug candidate failures, there continues to be a significant unmet need and an urgency from patients and providers for new therapies. We believe our key point of differentiation for Haduvio is the mechanism of action, which works synergistically both centrally in the brain and peripherally in the lungs. We believe this mechanism has the potential to work more broadly in RCC patients and potentially have a stronger effect across the broader range of baseline cough counts than peripheral-only mechanisms. Our RCC trial is the standard Phase 2a crossover design that has been conducted across several cough trials run to date and is planned to enroll approximately 60 patients. These patients will be randomized with a 1:1 stratification or approximately 30 in each arm between those with 10 to 19 coughs per hour, moderate cough, and those with greater than or equal to 20 coughs per hour, high cough. This trial has been progressing nicely, and we now have approximately 80% of the subjects enrolled. Based on the current run rate, we expect to report data from this study in the fourth quarter of this year. However, I want to note that we currently have an imbalance in the enrolled subjects between the two stratification arms, i.e., the 10 to 19 and greater than 20 cough counts. The enrollment between the two arms has fluctuated throughout the study. This is important data to inform future development, and there may be a scenario where we get to our overall planned number of 60, but keep the study open a little longer to balance the arms. We are excited to complete the enrollment of this study and report the data in this important chronic cough condition. Next, an update on our lead program in IPF chronic cough. IPF is a serious end-of-life disease. Chronic cough is reported by approximately 85% of patients suffering from IPF and has significant physical, psychological, and social impacts. Cough may also be a risk factor that plays a role in the progression of the underlying disease. The constant lung injury, micro tears, and inflammation caused by persistent coughing may lead to worse health outcomes for patients. With no currently approved treatment options for chronic cough in IPF, patients and providers have an urgent need for new therapies. Our IPF chronic cough trial, CORAL, is a Phase 2b parallel arm dose-ranging study that will investigate three active doses of Haduvio and placebo. The study is a six-week trial in approximately 160 patients. We are conducting this study in multiple countries and sites to be able to complete enrollment in a timely manner. We now have the majority of our sites activated and enrollment is progressing nicely. We have great relationships with the investigators in the trial and are communicating with them frequently to ensure our study is top of mind. The next milestone in this study is to conduct a sample size re-estimation, SSRE analysis, when 50% of the patients complete. This analysis will be done by an unblinded statistician external to the company who will rerun the power calculations using actual data. We will get very limited information back, but we will be informed of one of the following three outcomes. One, continue on as planned with the current planned number of patients, reconfirming the original powering assumptions. Two, the drug is working within the pre-specified promising zone, but will require an upsize in the number of patients to maintain the power. Or three, the drug is not working in the pre-specified range and the company should consider stopping. We will announce the results of this analysis when we have the information, which we expect in the fourth quarter of this year. We continue to expect topline data for the full study in the first half of 2025, subject to the result of the SSRE. We are also conducting two important supportive studies this year, the human abuse potential or HAP study, as well as the respiratory physiology study. I will give you a quick update on both. The HAP study is currently 95% enrolled and will require one more cohort of dosing to complete. We expect complete enrollment and dosing in the third quarter, with data from this study reported in the fourth quarter. Finally, we have initiated a Phase 1 respiratory physiology study, which is being conducted to systematically measure respiratory function in varying levels of disease severity and IPF to help determine our Phase 3 patient population. To date, we have excluded sleep-disordered breathing patients in our clinical studies and we want to better characterize the safety overall in the patient population. The protocol has been approved in both the U.S. and the U.K., and the study has initiated patient screening. We expect to enroll approximately 25 patients who will be inpatient for 10 days. The primary endpoint of the trial is the effect of escalating doses of Haduvio on respiratory function as measured by minute ventilation. Secondary endpoint measures of additional respiratory functions are also included. As you can see, these studies have progressed nicely and data from these trials will be important to inform the development path forward for Haduvio in chronic cough conditions. I want to thank our team who have worked hard to keep the enrollment on plan. We look forward to completing these clinical trials and reporting out the data beginning in the fourth quarter of this year. I will now turn it over to Lisa to review our financial results, and we will open it up for any questions you may have.

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the three months ended June 30, 2024, 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 2024, we reported a net loss of $12.4 million, compared to a net loss of $7.1 million for the same quarter in 2023. R&D expenses were $10 million during the second quarter of 2024, compared to $5.8 million in the same quarter in 2023, which reflects strong clinical activity across all four of our trials. G&A expenses were $3.3 million during the second quarter of 2024, compared to $2.5 million in the same period of 2023, primarily due to increases in personnel and related expenses, market research costs, and information technology services. As of June 30, 2024, our cash, cash equivalents, and marketable securities totaled $69.5 million, compared to $83 million as of December 31, 2023. During the quarter, we issued approximately 1.5 million shares from our ATM, which was purchased by a single buyer. This cash inflow strengthens our runway post-data readouts on our current clinical trials. We continue to expect that our cash burn, excluding the proceeds from the share issuance, will average $9 million to $12 million per quarter in 2024, and we will have cash runway into 2026. This concludes our prepared remarks. I will now turn the call back over to the Operator for Q&A.

The first question comes from Annabel Samimy from Stifel. Please go ahead.

Hi. This is Jai Adam calling in for Annabel. Congrats on the progress this quarter. I had two questions. The first is related to RIVER chronic coughs. When you guys were designing the trial, did you use different powering assumptions for the different severity groups being studied, or are they powers of the same treatment effect? And then the second question is related to the human abuse potential study. Can you confirm that nalbuphine is not a scheduled drug while butorphanol is scheduled? If that’s the case, is there any reason to expect a dose response to likability for the ER formulation? Has there been any indication from the FDA that there is a plan to potentially reschedule nalbuphine ER? Thank you.

Yeah. Thank you, Adam. I’m going to let David answer the powering assumptions for each arm, and then I’ll take on the half question.

Yeah. No. Thank you for the question. So as you know, the primary endpoint in RIVER is the total population N of 60. So that’s the primary analysis. But you’re really requesting – what you’re asking about is the subgroup analyses. We made the same assumptions for the effect size in those subgroup analyses.

And then for the human abuse potential analysis, Adam, I mean, nalbuphine has been around for decades. It’s been unscheduled by the DEA, and it gets looked at regularly, and they continue to unschedule the drug. We also have a lot of information on it. All the preclinical work was done. We have our whole clinical database, etc. So we feel, based on what we know, the drug should remain unscheduled. There is sort of this last piece to bring it up to current standards, the human abuse potential study. I guess we’ll run the study. We’ll see the data. It’ll be part of the analysis. They look at sort of eight different factors, of which that’s one. But I would just sort of bring everyone back to, there are two pieces of the mechanism in our drug: mu antagonists, none of which are scheduled, and kappa agonists, none of which are scheduled. So it seems a little bit unusual. Butorphanol, just to draw that comparison, is a weak mu agonist/kappa agonist. We’re a mu antagonist/kappa agonist. So I don’t want to say there’s no scenario where that happens, but we’re feeling pretty good about our drug and have not seen issues with that. But clearly, you have to run the study and see the data, and then we’ll submit everything when we get it.

All right. Thank you so much.

Yeah. Thank you, Adam.

The next question comes from Thomas Smith from Leerink Partners. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking the questions, and congrats on the progress. Just on the respiratory physiology study, I was wondering if you could comment on your expectations on enrollment in terms of patient disease severity that you’re enrolling into the study. And then also just comment on the doses that you’ll be evaluating in that study and how that compares to what you’re looking at in the IPF and RCC studies?

Sure. I’m going to let David take that.

Thank you very much, and thank you for the question. So the doses we’re studying are the same that we have in both RIVER and CORAL. We’re studying up to 108 milligrams BID in that inpatient study. And sorry, the first part of your question was...

Disease severity, healthcare...

So we start the study in essence in the same population which we’re studying in CORAL, the IPF diagnosis which is essentially the same population. And then once we have data from that initial group, we would expand the population, as we’ve disclosed previously, to include sleep-disordered breathing subtypes. So that would be added onto the study, including all varieties of sleep-disordered breathing in that study so that we can address the primary question, which is for Phase 3, we would like to include a broad range of IPF patients in Phase 3 so we can address that question.

Got it. That’s helpful. And then just, if I could ask a follow-up on RIVER, I was wondering if you could just elaborate on the enrollment balance between the moderate and severe patients that you’re seeing. Are we seeing more moderate or severe? And are there any other baseline characteristics that you have visibility into that maybe differ from your initial expectations or some of the other contemporary Phase 2 RCC studies?

Yeah. So we don’t comment, Tom, on all the sort of specifics within the trial midstream because things go back and forth. I would say there’s sort of a bit of an imbalance, but that’s gone both ways. At one point, one arm’s a little further ahead than the other. So we’ll sort of lay all that out by subgroup when we get to the end. I would say, as far as baseline characteristics, I can tell you when Meg came in, she went through sort of all the subjects enrolled and all their medical information. And David, you can comment as well, and felt it looked good, good diagnoses, nothing unusual based on what she saw.

Absolutely right. This is what we anticipated. One of the benefits of these smaller Phase 2a studies is that you can conduct trials at highly specialized centers, and that's exactly what we expected and have observed.

Yeah. Thank you, Tom, for the question.

That’s helpful. Yeah. Thanks for taking the questions and looking forward to the Q4 updates.

Great.

The next question comes from Leland Gershell from Oppenheimer. Please go ahead.

Hey. Good afternoon. Thanks for taking our questions. I just want to ask, as you think about the evolution of the development programs and we’re coming up on the RCC topline data, and as you continue developing Haduvio in IPF chronic cough, would the outcome of the RCC trial impact upon your plans in IPF? In other words, would you look to prioritize Haduvio in RCC? Would that alter kind of the weight you put on the IPF opportunity? Just wondering how you think about those two side-by-side should RCC print out a strong data set? Thank you.

Yeah. It’s a good question, Leland. We talk about it a lot as a team and a board. There’s a big commitment inside Trevi to that IPF is our lead indication. Severe unmet need, not a lot of options for those patients, cough is a big problem. We also, as I laid out in my comments, we believe that cough is potentially contributing to the underlying disease, and so how we might sort of look at some of those endpoints in an exploratory way. RCC is interesting because there is unmet need there, and how that eventually merges with IPF is sort of a question we’ll have to wrestle with. I think as Trevi, we would look to probably pick up sort of the most, assuming the P2X3 camlipixant gets approved, we would probably look to be a third-line therapy behind that for the failures, because we’d want to maintain the pricing we have in IPF. We think today that’s probably the optimal way to maximize the value of the drug. Now, in somebody else’s hands that’s got a bigger sales force, that may not be the case. So I would think about this, assuming the data supports it, that Trevi is going to be leading with its IPF program and studying RCC with an eye towards picking up the most severe coughers that aren’t getting relief anywhere else. And that could be, by the way, in this moderate cough count, if they’re not able to be treated. But that’s, we’ve done some modeling this summer, and I think that’s how we believe we could best optimize it.

Great. Thanks very much for the color.

Yeah. Thank you, Leland.

The next question comes from Mayank Mamtani from B. Riley Securities. Please go ahead.

Good afternoon, team. Thanks for taking the questions, and congrats on the progress. On the Phase 2a RIVER protocol, could you just remind us how that differs from the Phase 2a CANAL that you previously executed on very successfully? And then I’ll have a quick follow-up.

Thank you so much for the question. So the design, as you know, is in essence the same. The only difference we made is based on the early efficacy signal that we saw in the CANAL design, where we went up to 162 milligrams BID. We capped the dose at 108 BID. So the dose we reduced compared to CANAL, and we increased the washout period up to three weeks. There’s another minor difference as well. CANAL was run when COVID was very active, and we could only get the objective cough endpoint at baseline in week three. Here, we’ve gone back to the method we were able to get weekly objective cough data, which was always the aim in CANAL, but COVID got in the way.

Very helpful. Thank you. And then on the PROs, which we all know is an important regulatory topic also, could you just remind us what you’re looking for in CORAL, obviously? And then is RIVER also going to give us some more information on some of these PROs? And then I have one more question after that.

Yeah. David?

Yeah. So we increased the range of PROs, and I’ll start with the CORAL study first, compared to the CANAL study. So in CORAL, we basically have the opportunity to profile both with cough frequency score, that we’re using the exact, which was the same endpoint we used in Phase 2a in CANAL. But we’ve also expanded quite broadly, living with IPF. A lot of PROs, which allow you to get a good feel for the overall clinical characteristics and the improvements, including functional improvements that you get. So we’ve got a broad range of PROs. So less the cough questionnaire you would expect. Living with IPF is a very good instrument. And then standard anchor measurements, patient’s global impression of severity and change in cough and IPF. Those are the sorts of measures. Those are some of the most important PROs we added there. And we took a similar approach, frankly, even in the small RIVER study. So there, the important secondary endpoints of PROs would be cough frequency again, living less the cough questionnaire, and cough severity. We’re using the VAS measurement because that’s used in the majority of RCC programs, so it’s a good comparison to other programs. We may at some stage switch to the cough severity NRS measurement because, regulatory-wise, that’ll probably be a better endpoint for approvals, but that’s a relatively small detail. So, and then again, good anchor with patient global impression of severity and change in cough in the RIVER study as well.

Very helpful. Thank you. And then lastly, on your earlier comment, Jennifer, on the focus on severe cough cohort or maybe refractory to P2X3. Is that a more recent development, or is that something that you’re just going to be data-dependent on what you learn from RCC? And I just ask that because your final dose-ranging work could give you a different dose in those two different indications. So…

It's a great question, Mayank. As I mentioned, we have been discussing this quite a bit. It stems from some work we did over the summer, and you're correct that our decisions will be data-driven. Both conditions highlight significant unmet needs, presenting numerous opportunities. As a small company, we've found that for IPF, we can navigate through the entire approval process, and if we were to commercialize it, we'd require a specialized sales force, which we are confident in managing. In contrast, RCC complicates the situation. Our colleague has been exploring how to sustain the premium pricing we aim for in IPF within the RCC market. However, those decisions are not finalized. Our current thought process is based on some research done over the summer about how to optimize our approach without affecting IPF. Nevertheless, the RCC market is substantial enough, and I believe that in the hands of another company with an established sales force, they might be able to launch more extensively given that they wouldn't incur the costs of building one from scratch. You are correct that our approach will depend on data, and we do not have to make a decision for some time. We will proceed and conduct the next study, but eventually, we will need to address this question.

Yeah. Makes a lot of sense, and good to be ahead of that. Thanks again for taking our questions and looking forward to your future updates.

Yeah. Thank you, Mayank.

The next question comes from Brandon Folkes from Rodman & Renshaw. Please go ahead.

Hi. Thanks for taking my questions and congratulations on all the progress. Maybe just firstly on the HAP data readout, in terms of a positive outcome, is it really as long as we don’t see a dose-dependent likability—that that’s a positive outcome for you and strengthens your discussions with the agency? So that even if we see high likability in one of the groups, I’m sure we’ll see some likability. But as long as it’s not dose-dependent, should we interpret that as a positive and strengthening your discussion with the agency?

So, Brandon, that’s a good question. Like all data, it’s sort of the gestalt of what you see. I would say, there’s a published paper Cara did with their kappa agonist, where they showed separation from placebo, but they were less likable than their comparator pentazocine. They only had one dose, so the dose-response question wasn’t there. That drug was left unscheduled. So I think at a baseline on data, we will likely separate from placebo, but hopefully be less likable or similar to our comparator. I think that puts us in a strong situation. Now, having said that, you are right that what the FDA really has concerns, is if there’s a little bit of signal in likability, that you don’t see the dose dependence because you don’t want to see somebody like it a bit, and then you take sort of 3x the dose, and they like it three times more. So it’s a bit of all of that combined. So it’s certainly something we’ll look at. But our expectation is this drug should not be all that likable. I mean, you’ve looked at our adverse events profile and we just don’t see that. So when we get all the data, we’ll lay it out for the street and also have an expert to help sort of interpret what we’ve seen and our own conclusions around it.

Great. Very helpful. And then maybe just shifting gears into the respiratory study, in a way to characterize what you think the hurdle right here is to include sleep disorder patients going forward, or is it also a case of generate the data and then have the conversation with the agency in terms of whether it’s enough to get these sleep disorder patients or do you think there’s a finite hurdle here that the agency wants to see?

Regarding the respiratory physiology study, I think there are well-established endpoints and markers of what is a clinically relevant change in minute ventilation, which, for example, is the primary endpoint which we can utilize. So actually, we think the signal of the study will be relatively interpretable ourselves when we get this because, in clinical practice, there are fairly clear guidelines as to what is a clinically relevant change in all the endpoints we’re looking at. So we believe that the results of the study will be interpretable by ourselves. I don’t — it’s definitely not our thinking that we have to — it’s mandatory that we have to go back to the FDA and have some discussion. As part of an end-of-Phase 2 meeting, we’ll have this data set, but we think it’ll be more straightforward than, no, here’s a detailed discussion about the relevance of all these findings.

Thanks. That’s very helpful. And then maybe lastly, just following up on a few of the earlier comments, just on the RIVER imbalance between the two arms. You talked about how this has fluctuated throughout the study. Is this just a normal part of the fluctuation and of that cycle, or has one patient group become a little bit more competitive to enroll going forward? I know you’re not giving color on which patient group, but is there sort of a fundamental competition for one of these patient groups, or is it just normal fluctuation? Thank you.

So we always expected—you’re always going to get one group’s going to recruit a little bit faster than the others, but we expect – we weren’t predicting which one, frankly. The difference here that Jennifer was speaking to is the difference was a little larger than we expected. And that’s why, as we’ve always explained, we think approximately 30 subjects per group in these two subgroups, the 10 to 19 and the greater than 20 patients, will allow us to detect a clinically meaningful effect size. We’ve got more than 80% power in both of these subgroups with about approximately 30 subjects to detect a mid-30% effect size on top of placebo. And for that reason, we think it’s important to stick with that stated aim, and that’s what Jennifer was speaking to. So the difference was—the imbalance was a little bit larger than we were expecting when we started the study, but we always knew there’d be one group that would recruit quicker.

And it’s a difference of a month or two of recruiting. So, we’ll just see how it comes together. This issue could go away. I’m just reminding people of the protocol and that that could come up at the end of the study.

Thank you very much. Very helpful as always.

Yeah.

And congrats on the progress.

Thank you, Brandon. Nice to have you following us.

The next question comes from John Gionco from Needham & Company. Please go ahead.

Hi. This is John on for Serge today. Thanks for taking our questions. First, surrounding the IP for nalbuphine, can you provide an overview of the current patent coverage and if any additional applications are outstanding at this time and whether the existing method of use IP applies equally to both IPF and RCC?

Yeah. Good question, John. Thank you. So, we have issued method of treatment patents. We have a set of formulation patents that protect the product till roughly 2030, but we have issued method of treatment patents, which is really the core of the protection that are issued through 2039 for IPF costs. We do have worldwide rights and patents that we’ve prosecuted around that. There are some additional applications being prosecuted as well concerning other clinical work we’ve done around the label, things like dosing in the elderly or hepatically impaired, renally impaired, probably get some IP maybe out of our human abuse potential study. So those kinds of patents that are being prosecuted now would actually extend this out to one group’s 2041 and one group’s 2043. But I think of this sort of the core of the patent coverage through this method of treatment 2039. As for refractory chronic cough, that broadly falls under the same umbrella. We’re waiting for our data out of this RIVER study, and then we’ll prosecute the actual claims around the data we saw, file them as track one claims, and those should be issued as well. We wrote the overall invention with it in mind that we would be looking at IPF, other interstitial lung diseases, and refractory chronic cough. And we pull from that application when we get actual data to get the claims issued.

Great. Sounds good. And just a quick follow-up. If you could discuss the current patient population with regard to RCC in terms of how many are diagnosed and how many are currently seeking treatment, just to provide a little granularity on that? Thanks.

Yeah. Good question. And we have some of this in our corporate deck, and I don’t have my commercial colleague on. We believe there are about 2 million to 3 million treatable patients in the U.S. It’s a big indication. I think there’s roughly 7 million patients diagnosed in the U.S. But when you sort of work that down of people who are looking for treatment and not getting proper care, it brings it down to about 2 million to 3 million patients. But if you want to, John, we can follow up on that, and I can have Farrell join the call, and we can give you a better walk-down. Thank you for the questions.

The next question comes from Debanjana Chatterjee from JonesTrading. Please go ahead.

Hi. Thanks for taking my question. Are you able to hear me?

Yes.

Yes. Okay. I was kind of curious, like, how long of a delay do you anticipate to the RCC readout because of this imbalance? And I have a follow-up question.

I don’t — I mean, sitting here today, I don’t expect any delay. We’ve confirmed — reaffirmed our guidance for the fourth quarter of this year. We are 80% enrolled. So, I just only bring up the issue because if we get to the end and want to hold the trial open for, I mean, we’re not going to hold it open for more than a month or two at the most to get these arms in balance. And it may not even — that may not even be required. So at this point, I don’t expect any delay. I’m just pointing out that that wasn’t a part of our protocol we really wanted to try to execute on to get the information.

Yes, that’s very helpful. Thank you. I have another question. You mentioned that if you decide to lead the RCC program on your own, you could consider third-line. How significant do you think the opportunity size is there? What is the patient count?

Yeah. So we have not shared all of that. We’re doing a lot of work this summer. It’s a big patient opportunity. I mean, with a lot of the P2X3s. I know you followed that space, Debanjana. They don’t work in sort of 30% to 40% of the patients. Some of the patients they work in have very severe cough, and even then, with the reduction in cough, it’s not completely reduced. So there’s a pretty big opportunity here for this group with really not a lot of options. So we are finishing up our market research. And at some point, we’ll share sort of our views on that and how that walks down. But we view that as a very significant market opportunity, particularly in light of the fact there’s very little—there’s not a lot of competitors left in the space.

Yeah. Thanks a lot.

Yeah. Thank you.

This concludes our question-and-answer session. I would like to turn the conference back over to Jennifer Good for closing remarks.

Thank you for joining us. We are expecting steady news flow of data in the upcoming months regarding our clinical trials data, and we look forward to sharing this with you. We will be participating in several investor conferences over the next couple of months, as listed in our press release, and hopefully, we will see some of you there. Thank you for joining the call, and we’re available afterward for any questions you may have.

The conference is now concluded. Thank you for attending today’s presentation. You may now disconnect.