Trevi Therapeutics, Inc. Price & Performance (TRVI)

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 fourth quarter and year end twenty twenty four earnings call and business update. Joining me today on this call is my colleague, Lisa Delfini, Trevi's Chief Financial Officer. Lisa and I will make some comments on the business and financial results, then we are happy to answer any questions that you may have. 2024 was a strong year of execution by Team Trevi. Which delivered three positive data readouts over the past few months, The Human Abuse Potential Study, the Sample Size Re Estimation, for the CORAL study in chronic cough patients with IPF, and the RIVER study in patients with refractory chronic cough, or RCC. These trials in total were conducted across 11 countries in approximately 75 different sites and through multiple regulatory authorities. I am proud of our team and the urgency and commitment they had to running high quality trials. Each of these trials had data analyses that were very important to advancing the clinical development plan of Haduvio. Me briefly review each of these key readouts.

In December, we read out positive results in our human abuse potential or HAP study. We needed to bring the package on drug likability up to current day standards [indiscernible] As a reminder, injectable Nalbuphine, which is indicated for severe pain, has been around for decades and continues to be unscheduled by the DEA. Bufene belongs to a class of drugs known as mixed agonist antagonists, that were designed for patients to get the efficacy of opioids but without the abuse potential. There are two primary reasons for Nalbuphine remaining on schedule all these years. First, because of the mu antagonism effect of the drug, which can elicit withdrawal symptoms in individuals who are abusing opiate class drugs it is not preferred or sought after by these individuals. Second, in the DEA's ongoing surveillance, there are no significant issues of abuse detected. Both the one hundred and sixty two milligram and the eighty one milligram now buphine doses studied shows statistically significant lower relative drug liking compared to butorphanol. Based on the effective doses that we are seeing in cough, it is likely that the one hundred and sixty two milligram dose fulfills the requirement of 3x the marketed dose to be considered supratherapeutic.

There's nothing else we need to do until filing our NDA when we will submit an eight factor plan which will include this data. And a final determination on whether there will be changes in scheduling will be made upon approval by the FDA and DEA. We do not believe we have shown anything in our program that changes the abusability risk profile of this drug and that it will remain unscheduled. But that decision will ultimately be made later. Moving on to our clinical data. In December, we announced the results of the sample size re estimation or SSRE analysis in our Phase 2b study in patients with IPF chronic cough.

This was a preplanned statistical look on the highest dose arm, one hundred and eight milligrams BID, when fifty percent of the originally planned patients completed the six weeks of treatment to confirm the original powering assumptions. The analysis was done by an unblinded statistician external to the company. The only information we received back was regarding whether change to sample size was required. We were very pleased with the result that the SSRE confirmed the original sample size of 160 patients. This positive result essentially confirms the assumptions of effect size of the study expected variability, and confirmed a conditional power at the 50% enrollment point of at least 80% or greater. This was exciting news for us and allowed us to stay on the original timelines for the study and wrap up enrollment in February of year. Just a little color on enrollment. We had our biggest month of enrollment in December and January, which I think speaks to the excitement about a potential treatment and the significant unmet need in these IPF patients suffering from chronic cough.

We currently have a handful of patients completing their treatment and expect to announce data from this trial in the second quarter of this year. This is our lead indication and we are excited to get the data from this dose ranging study and advance the development program. Finally, just last week we announced the data from our Phase 2a RIVER trial in patients with RCC, which includes those with unexplained chronic cough. RCC is a debilitating disease that affects approximately two to three million U. S. Patients and has no approved therapies in U. S. Importantly, there have been many drugs studied in this condition which have failed all primarily peripherally acting agents, with only one drug still in late stage development. Our hypothesis heading into the RIVER study was that our central and peripheral mechanisms could change the outcome for patients that suffer with this disease. The types of chronic cough we are studying are linked through hypersensitivity at the brain, and why we believe the central aspect of our mechanism is important. As reported last week, Haduvio met the primary endpoint in the RIVER study with a statistically significant reduction in twenty four hour objective cough frequency achieving a p value of less than 0.0001 with a 57% placebo adjusted change from baseline, and importantly showed the same strong effect across a range of cough counts including patients with moderate or severe cough.

So, we are excited to progress development of Haduvio in RCC. As we have explained, with IPF as our lead indication, and a specialty commercial sales model, we will develop Hiduveo and RCC for patients which have failed prior therapy. We believe there are many patients not getting relief from the drug currently being used off label and even if a P2X3 antagonist is approved, they have only been shown to work in the most severe coffers. Which represents less than a third of the market. So, there will still remain a high unmet need for RCC patients who have exhausted available treatment options. By moving to treatment failure patients in RCC, we focus on the patients with the highest unmet need allowing us to target a subsegment of the RCC population and maintain our specialty IPF pricing. So, data readouts at Trevi have been on a roll.

Next up is our Phase 2b readout for the CORAL trial in IPF chronic cough patients. As I mentioned, we expect that data next quarter. The team has been busy planning for the next steps to quickly progress development of Hiduveo in both IPF and RCC. The next key steps in development are for the IPF cost program, we will get the data and assuming it is is positive, we'll prepare for an end of Phase two meeting with the FDA. Which we expect will happen by the end of twenty twenty five. At the meeting, we expect to discuss our planned pivotal program, study designs and required safety database as well as any other development studies we need to do for an NDA filing. For the RCC program, we are waiting on final data sets and developing a protocol for the next study. We will request a meeting with the to get their input on our program and next study. We are planning on releasing more of the RIVER data at both the American Thoracic Society meeting in May in San Francisco, as well as the European Respiratory Society Congress meeting in September. As a side note, we are planning on being quite active at ATS in San Francisco in mid May.

So if any of you plan to attend, please let me know. We are planning on hosting a KOL panel featuring both IPS experts and an RCC doctor for investors. As you can see, we made a lot of progress this year and Haduvio is now the first and only therapy in clinical development to show a statistically significant reduction in chronic cough across patients with IPF and RCC. It positions Hiduveo as a first in class therapy in IPF and potentially best in class across chronic cough indications. We have a focused plan on developing Haduvio in serious chronic cough conditions that our team can execute and we believe can generate significant value for the company and its shareholders. 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 and twelve months ended December 31, 2024, can be found in our press release issued ahead of this call and our 10 ks, which was filed with the SEC today after the market closed. For the fourth quarter of twenty twenty four, we reported a net loss of $11,400,000 compared to a net loss of $7,800,000 same quarter in 2023.

R and D expenses were $9,300,000 during the fourth quarter of twenty twenty four, compared to $6,500,000 in same quarter in 2023. The increase was primarily due to increased clinical trial costs in our Phase 2b CORAL trial, our Phase 2a RIVER trial, and our HAPP study as well as an increase in personnel related expenses. G and A expenses increased to $2,900,000 during the fourth quarter of twenty twenty four compared to $2,400,000 in the same period of 2023, primarily due to an increase in stock based compensation and personnel related expenses. As of 12/31/2024, our cash, cash equivalents and marketable securities totaled 107,600,000.0 This included a $50,000,000 unwritten we completed in December after the two positive data readouts that Jennifer discussed. This set us up nicely to not have to raise off of our positive RCC data last week. Our cash runway guidance into the second half of twenty twenty six remains unchanged and funds completing our ongoing Phase 2b CORAL trial for chronic cough in patients with IPF, and based on our current estimates, our next RCC trial. It does not include funding for the next studies in IPF other than some start up costs. In 2025, we expect cash burn net of interest income of about 12,000,000 to $14,000,000 per quarter in Q1 and Q2.

Over the next couple of quarters, we will be getting feedback from the FDA and planning the subsequent trial in RCC and assuming positive data trials in IPF and non IPF ILDs. We will give additional cash burn guidance as we provide guidance on the design and start date for these trials. Our current fully diluted shares outstanding are approximately 137,000,000, which includes approximately 10,000,000 stock options outstanding. This concludes our prepared remarks. I will now turn the call back over to the operator for Q and A. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touch tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star and then 2. Due to the number of participants on the call, questions will be limited to one per caller, and any relevant follow-up to your question. If you have other you may get back in the queue. At this time, we will pause momentarily to assemble our roster. The first question comes from Fashel Khershid with Leerink Partners. Please go ahead. Hey, good afternoon. Thanks for taking the question.

I wanted to ask, now that you've completed enrollment, in CORAL, could you speak a little bit to the patients that you enrolled? Specifically, like, there any differences in the first half of the study before the sample size estimation and the second half of the study like this kind of bolus that you talked about in December and January until you completed the enrollment? And then I have a follow-up. Thank you.

Thank you, Faisal for the question. So you remember, we didn't get the results from this till December and the study was almost 75%, 80% enrolled at that point. So, didn't make any change because until we knew those results, even then we didn't change any sites, no protocol changes. The overall study statistics look basically the same. So that's an important aspect of this. We did not share these results with the sites other than to say that we did the preplanned analysis and no upsize was required because you don't want to sort of change script they're using at the site. So, now we've been very careful to not have any changes in the second half of this population.

Got it. Helpful. And I think before you kind of commented a little bit on the discontinuation rate that you were seeing kind of earlier on, in Coral. Could you comment that now that you're almost done with the study dosing, how that's tracked in kind of the back half of the study?

Jim confirmed to me about an hour ago that we're still running in single digits. So it stayed very consistent actually in the whole study, and that's total. We can only see total blinded. So, I don't obviously know who's on drug and placebo, but, we stayed in single digits and it stayed very consistent across the study.

Awesome. Thank you. Looking forward to the data.

Yeah. Thank you, Tessa. And the next question comes from Mayank Amtani with B. Riley. Please go ahead. Yes. Good afternoon, team. Thanks for taking our questions and congrats on strong execution in recent months. Could you talk a little bit about your placebo response expectation for IPF chronic cough Phase II study? And if you could confirm the two week placebo run-in period that you have, and how might your sorry, multipart question how might your baseline cough count differ from what you had in CANAL? Yeah, so, just first of all, the two week placebo run, and that's not a two week placebo run-in, that's a two week titration period. Which we will have in all of our studies. So, to be clear about that. Placebo hasn't been a big problem in IPF studies to date. It's been pretty well behaved. So, we didn't see a need to do any kind of placebo run-in. The powering assumptions around placebo we had assumed 66% drug effect, 30% placebo. RSS so 36% placebo adjusted change. As you know, our 1523%. So, I think we've been pretty conservative there. And then as far as baseline cough counts, we are not our medical monitor is looking at that, but I'm sure certainly not looking at that at my level, and I don't think Jim is either.

So, don't have any commentary around what baseline cost counts look. I do know that our inclusion criteria of how you get in and sort of there's some minimum baseline costs that are required of VASc score. Didn't change. So I would assume that we should be roughly in the same range.

Thank you. And if I could maybe ask about the River RCC data that now that it's out and being looked at by KOLs, how are you thinking of the RCC patient population being split between P2X3 and Haduvia, assuming, you know, they both are on the market sort of the next three to four year time period? Thanks again for taking the question.

Yeah, thank you, Mayank.

As we said on commercially, we're looking at being treating basically patients that are treatment failures. So right now they're all being used They're all being tried with off label stuff that really doesn't work that well. So, all the patients ending up in these studies have already been through sort of that layer of stuff. If a P2X3 does make it to the market, Glaxo has success and I hope for patients that they do. I think we will look to you can try your P2X first, but then if you fail that, you'll get to our Haduvio therapy. So, second or third line therapy depending on what's approved. I think there's a lot of unmet needs still. I think, as you know, the P2X3 really only had success in the severe coughers and even then haven't shown efficacy in forty percent of those. So there's a lot of people who are still seeking treatment and this moderate and severe is somewhat on arbitrary line. I think the people that are really pursuing therapy are not able to get treatment that helps them. I think they'll end up in trying our Haduvio.

Thank you.

Thank you.

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

Hi, thanks for taking my questions. Just some more data now that you more questions around the data now that you've had about ten days to mull it over. Is there anything you can share with us regarding the efficacy that you saw maxed out at the fifty four dose and if this was similar to what you saw in the initial trial? Did you see a maxing out of that? And if you might still be considering you know, possibly lower dosing in the CORAL studies. I understand that you have to see it, but it seems if you had any maxing out in canal, it might indicate that you might see potentially look at lower doses there. And I say this I guess with the AEs in mind and how that might be improved these AEs based on initial treatment or did they come as they stepped up in dose? So I guess that's my first very long question.

Yeah, no, I get it. All good questions. I think Annabel, we haven't seen any more data since the top line data we got I mean, it's hard to believe it was ten days ago. It feels like two days ago. It's been a blur. But I would say that I think the difference of canal are first IPF study in here, we did not have vitallo JAK readings at each dose We had to rely on patient reported outcomes and there was a similar slope, but it did seem to show efficacy on the pro through one hundred and eight milligrams In this study, you're right, it sort of clearly shows that appears the effective doses in that twenty seven to fifty four range. The CORAL results in IPF, the parallel arm design is going to be very informative, I think around dose. So, I definitely think and Jim and I have talked about this as well. Probably the one hundred and eight milligrams for RCC we will not need. We will end up on the low end of this dose range, which is always advantageous. In the direction you were heading around to AEs. You can titrate slower, you can do one time dosing at night for a while to get people used to the drug.

It just gives you a lot more flexibility when you're not trying to move people up to higher effective dose early. So, yeah, we don't have more data when we do, we'll show some of that color. Probably that's some of what I'm going to share at ATF. I think. But that's what we know today. Our CMC team is looking at the doses and thinking about whether we might even need one dose lower than twenty seven. So, we're doing some planning around that as well.

Got it. Then just really quickly on the RCC, the next trial.

Will you be is it also still going to be an all comers trial refractory population? Are changing the inclusion criteria at all, given that you are sort of positioning this for a third line treatment after P2X3s, I guess you don't really have the opportunity to position it that way in a trial. But is there anything about the inclusion criteria or the populations that you might be studying in the next trial?

No, so in our inclusion criteria it'll be really similar to what we just did. There's got to be some minimum level of cost. People have centered around this eight to 10 costs because we're not trying to go after this mild intermittent population. But other than that, we're no longer delineating between moderate and severe. The cough world doesn't do that. It's sort of an arbitrary thing that was made up for clinical trials. And so we'll just move forward, which I think gives us a lot of advantages in recruiting and flexibility. So, I think that will be quite helpful. And there was a second part of your question, I'm sorry, which I forgot.

Oh, no, you pretty much covered it. [indiscernible] you. Thank you. One other point which slipped my mind, but thank you, Annabel.

Okay, thanks a lot.

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

Hey. Good afternoon, Jennifer and team. Thanks for taking the question. Wanted to just ask with respect to timelines, I know when we checked in last, which was before the river readout, know, in addition to the efficacy data, you'll also need kind of long term exposure data, to fill out the NDA package.

Which would sort of impact, initial approval timelines. I'm just wondering if you were pursuing RCC in a Phase III and you also have what I guess would be two Phase III's for IPF cough. Could that expedite your route to market cause you may have additional safety exposure data from the patients who come from the late stage RCC study. Thanks.

Yeah, that's a good question, Leland. So, today we haven't done any open label extension data. We need to start doing that from here on out. As you know, our regulatory strategy is our first NDA is currently planned to be the study. So that will be the NDA that we negotiated with the FDA about what kind of safety database exposures they need. RCC will be an SNDA, so it's a follow and we'll get to benefit from all the exposure data that was developed around IPF and is just one pivotal study in that strategy. So these are the kinds of things we need to really sit with the regulatory authorities and talk through. As you also know, we have a lot of safety data from our prior clinical programs. Which includes six months and twelve months safety data. So, how that all folds together, we'll have to sort through because I think our actual efficacy trials will not need to be very big with this effect size. It will really probably be driven more by the safety database.

Okay, thanks for the color.

And I'm just going to follow-up. Annabelle, remembered your second question, which was around treatment failures. And, just to sort of finish that point, these people have all failed now and I think in the next study, it will just be a matter of documenting that they've tried other things and they failed on another anti test of therapy. And so that will start going into our protocols and will satisfy that requirement from a development perspective.

Next question.

And the next question comes from Serge Belanger with Needham and Company. Please go ahead. Hi, good afternoon. I guess my first question regarding the just an update on the respiratory physiology study. Whether it's on track I guess, to finish in the second half and if you're it's been modified given the recent data from NRCC.

Yeah, it's a good question, Serge. So that study screening is underway. There's been some, I would say, just operational logistics of sorting out certain things. It's a study nobody has done. So again, just typical Phase I kind of stuff. We have two good sites and have kind of worked through that. Jim is back contemplating whether we need the one hundred and eight milligram dose and study. So that's sort of in the works now, I would say. We were dosing up through one hundred and eight, but I think there's some thinking that maybe we need that study or that dose after all. So it's ongoing still on track to be ready for our end of Phase two meeting when we, go in and discuss our data and our past forward with the agency.

Thanks.

Thank you, Serge.

And the next question comes from Ryan Desitsner with Raymond James.

Please go ahead.

Hi. Thanks for the question.

What exploratory metrics do we expect to see at the time of the 3Q IPF chronic cough readout, specifically thinking about exact question two or sleep, cough frequency? And then I have a Yeah, Ryan, so that's a good question, which I, don't know specifically. I know in top line we'll obviously get the primary endpoint some of the key secondaries. Exact two will definitely be there because that's one of the key secondary studies in the endpoint as well as I think CFVAS. But beyond that, I don't know if we're getting any of the other secondary endpoints.

Okay, and then looking ahead to a late stage RCC study, what potential stratifications like call frequency, for example, would you consider based on what you've learned so far from River?

Yeah. My team here is waving at me too. Apparently you said q three for data. It's q two, just so, we're all talking the same language. Yes, our plan going forward in RCC is no stratification. We saw virtually no difference in effect between moderate and severe. Obviously, we'll go through individual patient data, but it was strong and with our mechanism, that's what we expected. It's also what we saw in IPF cough. We're not planning to stratify at all between moderate and severe.

Got it.

Looking forward to the 2Q readout.

Yeah, thank you, Ryan.

The next question comes from Brandon Fowe with Rodman and Renshaw. Please go ahead.

Hi. Thanks for taking my questions. Maybe just sort of from me, just following up on the placebo rate. Any scientific reason why the placebo rates in 10 to 15 centers, high end cost centers, really high end thought leaders in the space. IPF is a little more sort of out into normal IPF centers that are doing lots of studies. So, is no I don't have a good scientific reason. And Jim got asked this question last week and we didn't have a good answer. I think the good news is these are generally within sort of what we had planned. The RCC study was very tight, but we will certainly plan for higher placebo rates in the parallel arm next study.

Great. Thanks very much for taking my questions, and congrats on all the good data. Of late.

Yeah. Thank you, Brandon.

And the next question comes from [indiscernible] Steer Street. Please go ahead.

Hi, this is Chris I'm on for Kaveri today. Congratulations on your recently presented R data.

And just going forward, I guess across indications, could you tell us what secondary endpoints you think will matter most for driving Haduvio prescriptions and having less payer resistance?

Yes, so it's a good I think there's some work being done around patient secondary endpoints. I think the first question is making sure the FDA is happy that your key secondary is linked to your primary endpoint of objective cough. That seems to be centering around cost severity, which isn't quite the same thing as cost frequency. When you get to payers and things, things like metrics like quality of life for the patient matters. But our commercial guys involved in sort of these next studies and which metrics will be built in as secondary endpoints. But it will be across between sort of the severity scales and then some of the quality of life metrics as well.

Got it.

Thank you.

Thank you, Christian.

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

Thank you. We look forward to the upcoming results of our 2b CORAL trial next quarter and appreciate you joining today's call. Lisa and I are available after the call for any follow-up questions you may have.

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