Trevi Therapeutics, Inc. Q4 FY2024 Earnings Call

Good afternoon and welcome to the Trevi Therapeutics Fourth Quarter and Year End 2024 Earnings Conference Call. At this time, all participants will be in 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 Factors section of the company's most recent annual 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 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 2024 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, 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. Let me briefly review each of these key readouts. In December, we readout positive results in our Human Abuse Potential or HAP study. We needed to bring the package on drug likability up to current day standards since nalbuphine is a centrally acting therapy. As a reminder, injectable nalbuphine, which is indicated for severe pain, has been around for decades and continues to be unscheduled by the DEA. Nalbuphine 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 unscheduled all these years. First, because of the neo-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 162 milligram and the 81 milligram nalbuphine doses studied show 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 162 milligram dose fulfills the requirement of 3x the marketed dose to be considered super therapeutic. 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've 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 reestimation or SSRE analysis in our Phase 2b study in patients with IPF chronic cough. This was a pre-planned statistical look at the highest dose arm, 108 milligrams BID when 50% 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 a 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 this year. Just a little color on enrollment. We had our biggest months 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 2 million to 3 million US patients and has no approved therapies in the US. Importantly, there have been many drugs studied in this condition that 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 mechanism 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 24 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 the development of Haduvio in RCC. As we have explained, with IPF as our lead indication and a specialty commercial sales model, we will develop Haduvio in RCC for patients who have failed prior therapy. We believe there are many patients not getting relief from the drugs currently being used off-label and even if a P2X3 antagonist is approved, they have only been shown to work in the most severe coughers, 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 sub-segment 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 the development of Haduvio in both IPF and RCC. The next key steps in development are for the IPF cough program, we will get the data and assuming it is positive, we'll prepare for an End-of-Phase 2 meeting with the FDA, which we expect will happen by the end of 2025. 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 datasets and developing a protocol for the next study. We will request a meeting with the FDA 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 IPF 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 Haduvio 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, 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 three and 12 months ended December 31st, 2024, can be found in our press release issued ahead of this call and our 10-K, which was filed with the SEC today after the market closed. For the fourth quarter of 2024, we reported a net loss of $11.4 million compared to a net loss of $7.8 million for the same quarter in 2023. R&D expenses were $9.3 million during the fourth quarter of 2024 compared to $6.5 million in the 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 HAP study as well as an increase in personnel-related expenses. G&A expenses increased to $2.9 million during the fourth quarter of 2024 compared to $2.4 million in the same period of 2023, primarily due to an increase in stock-based compensation and personnel-related expenses. As of December 31st, 2024, our cash, cash equivalents and marketable securities totaled $107.6 million. This included a $50 million unwritten offering 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 2026 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 startup costs. In 2025, we expect cash burn net of interest income of about $12 million to $14 million 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 million, which includes approximately 10 million stock options outstanding. This concludes our prepared remarks. I will now 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 Faisal Khurshid 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? And specifically like were 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 until December and the study was almost 75%, 80% enrolled at that point. So we didn't make any changes 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 pre-planned analysis and no upsize was required because you don't want to sort of change the script they're using at the site. So, no, we've been very careful not to have any changes in the second half of this population.

Got it. That's 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 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.

And the next question comes from Mayank Mamtani 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 2 study? And if you could confirm the two-week placebo run-in period that you have and how might your, sorry, multi-part question, how might your baseline cough count differ from what you had in CANAL?

Yes. First of all, the two-week period is not a placebo run-in; it's a titration period, which will be included in all our studies. To clarify, placebo has not posed significant issues in IPF studies to date and has behaved consistently. Therefore, we did not find it necessary to implement a placebo run-in. Our assumptions regarding placebo effects estimated a 66% drug effect and a 30% placebo effect, equating to a 36% placebo-adjusted change. Our SSRE confirmed that we at least meet that effect size or exceed it, suggesting we were quite conservative regarding the placebo effect. Historical IPF studies have shown a placebo effect ranging from about 15% to 23%. We've been conservative in that estimate. Regarding baseline cough counts, our medical monitor is reviewing that, but I'm not examining it at my level, and I believe Jim isn't either, so I can't provide insights on the baseline cough counts. Our inclusion criteria, which specify minimum baseline costs related to the VAS score, have remained unchanged, so I would expect we are in a similar range.

Got it. 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 Haduvio assuming they both are on the market in sort of the next three-to-four-year time period? Thanks again for taking the questions.

Thank you, Mayank. As we've mentioned, we are focusing on treating patients who have not responded to previous treatments. Currently, these patients are using off-label options that are not very effective. Those participating in our studies have typically already tried those alternatives. If P2X3 becomes available, and Glaxo finds success with it, we hope it benefits patients. Our approach may allow patients to try P2X3 first, and if it doesn't work for them, they would then have access to our Haduvio therapy as a second or third-line option, depending on approval. There remains a significant unmet need. P2X3 has mostly helped those with severe cough, yet it hasn't been effective for 40% of that group. There are still many individuals seeking effective treatment for moderate to severe symptoms who haven't found relief. I believe they will turn to our Haduvio therapy.

Thank you.

Thank you.

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

Hi. Thank you for taking my questions. Now that you’ve had about ten days to reflect, is there anything you can share about the efficacy observed at the 54 milligram dose? Was this similar to what you observed in the initial IPF trial regarding efficacy reaching a maximum level? Are you considering the possibility of lower dosing in the CORAL studies? I understand you still need to evaluate this, but any indications of a maximum effect in the CANAL study might suggest looking at lower doses. I mention this with the adverse events in mind; were these events related to the initial treatment or did they occur as the dose increased? So, that’s my first, quite lengthy question.

Yes. 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 10 days ago. It feels like two days ago, it's been a blur. But I would say that I think the difference of CANAL, our first IPF study in here, we did not have VitaloJAK 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 108 milligrams. In this study, you're right, it sort of clearly shows it appears the effective dose is in that 27 to 54 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 108 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 AEs. You can titrate slower, you can do once-a-night dosing 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 a higher effective dose early. So, yes, 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 ATS, 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 27. So, we're doing some planning around that as well.

Got it. And regarding the next trial for the RCC, will it still include an all-comers refractory population? Are you planning to make any changes to the inclusion criteria since you are aiming for a third-line treatment after P2X3s? I understand it may be challenging to position it that way in a trial, but are there any adjustments to the inclusion criteria or populations you are considering for the next trial?

No. In our inclusion criteria, it will be really similar to what we just did. There has to be a minimum level of cough. People have centered around 8 to 10 coughs because we're not targeting the mild intermittent population. Besides that, we're no longer distinguishing between moderate and severe. The cough world doesn't make that distinction; it was created arbitrarily for clinical trials. So we'll just move forward with this, which I believe will provide us with significant advantages in recruiting and flexibility. That will be quite helpful. I'm sorry, I forgot the second part of your question.

No, you covered it well. That's great. Thank you.

Okay. I was thinking one other point which slipped my mind. But thank you, Annabel.

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

Good afternoon, Jennifer and team. Thank you for taking my question. I wanted to inquire about the timelines. I know from our last discussion, prior to the RIVER readout, that in addition to the efficacy data, long-term exposure data will also be necessary to complete the NDA package, which could affect the initial approval timelines. If you are pursuing RCC in a Phase 3 and also have what would be two Phase 3 studies for IPF costs, could that potentially accelerate your path to market because you might obtain additional safety exposure data from patients involved in the late-stage RCC study? Thank you.

Yes, 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 IPF study. So that will be the NDA that we negotiate with the FDA about what kind of safety database exposures they need. RCC will be an SNDA. So it's a follow-on 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 6 months and 12 month 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. So it will really probably be driven more by the safety database.

All right. Thanks for the color.

And I'm just going to follow up, Annabel, I 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 antitussive therapy. And so that will start going into our protocols and we'll satisfy that requirement from a development perspective. Next question.

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

Hi. Good afternoon. My first question is about an update on the respiratory physiology study. Is it on track to be completed in the second half, and has it been modified based on the recent data in RCC?

Yes, it's a good question, Serge. So that study is screening, it's underway. There have 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 1 kind of stuff. We have two good sites and have kind of worked through that. Jim is back contemplating whether we need the 108 milligram dose in that study. So that's sort of in the works now, I would say. We were dosing up through 108, but I think there's some thinking that maybe we won't meet that study or that dose after all. So it's ongoing, still on track to be ready for our End-of-Phase 2 meeting when we go in and discuss our data and our path forward with the agency.

Thanks.

And the next question comes from Ryan Deschner 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 2 or sleep cough frequency? And then I have a follow-up.

Yes, Ryan, so that's a good question, which I don't know specifically. I know in topline, we'll obviously get the primary endpoint and some of the key secondaries. EXACT-2 will definitely be there because that's one of the key secondary studies in the endpoint as well as I think CS-VAS. 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 cough frequency, for example, would you consider based on what you've learned so far from RIVER?

Yes. My team here is waving at me too. Apparently, you said Q3 for data, it's Q2, 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 severes. 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. So, we're not planning to stratify at all between moderate and severes.

Got it. Looking forward to the 2Q readout.

Yes, thank you, Ryan.

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

Hi. Thanks for taking my questions. And maybe just sort of from me, just following up on the placebo rate. Any scientific reason why the placebo rates in IPF would differ versus RCC? Obviously, we've seen RCC data hearing the powering you mentioned earlier. Is that just sort of how the studies were designed, but just any scientific rationale we should think about when we see that data when we're looking at the placebo adjusted? Thank you.

Yes, I've received this question because the placebo rate in the CANAL IPF study was actually a bit higher than in the RCC studies, which seems counterintuitive. Typically, these crossover studies are rather consistent, so the placebo effect doesn't usually become apparent until we look at the parallel arm design. I believe this discrepancy may arise because RCC studies are conducted in the same 10 to 15 high-end centers, which are regarded as leading sites in the field. In contrast, IPF studies tend to be spread out across a wider range of standard IPF centers that conduct numerous studies. I don’t have a solid scientific explanation for this. Jim was asked a similar question last week, and we didn't have a clear answer then either. However, the good news is that these rates generally align with what we anticipated. The RCC study was very consistent, but we will definitely plan for higher placebo rates in the parallel arm of the next study.

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

Yes. Thank you, Brandon.

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

Hi. This is Christian. I'm on for Kaveri today. So congratulations on your recently presented RCC data. And just going forward, I guess, across indications, could you tell us what secondary endpoints do you think will matter most for driving Haduvio prescriptions and having less payer resistance?

Yes. So it's a good question. 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 secondaries are linked to your primary endpoint of objective cost. 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 matter. But our commercial team is involved in sort of these next studies and which metrics will be built-in as secondary endpoints, but it will be a cross 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.

This conference has now concluded. Thank you for attending today's presentation. You may now disconnect.