Participants
Jennifer Good; President, Chief Executive Officer, Director; Trevi Therapeutics Inc
Lisa Delfini; Chief Financial Officer; Trevi Therapeutics Inc
Faisal Khurshid; Analyst; Leerink Partners
Mayank Mamtani; Analyst; B. Riley Securities
Annabel Samimy; Analyst; Stifel Nicolaus & Co Inc
Leland Gershell; Analyst; Oppenheimer & Co Inc
Serge Belanger; Senior Analyst; Needham & Company LLC
Ryan Deschner; Analyst; Raymond James
Brandon Folkes; Analyst; Rodman & Renshaw
Presentation
Operator
Good afternoon, and welcome to the Trevi Therapeutics fourth-quarter and year-end 2024 earnings conference call. (Operator Instructions) 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.
Jennifer Good
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 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.
Let 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 after current day standards since nalbuphine is 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 new antagonism effect of the drug, which can elicit withdrawal symptoms in individuals who are using opioid 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 preplanned statistical look on the highest dose arm, 108-milligram 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 time line for the study and wrap up enrollment in February of this 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 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 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 mechanism could change the outcome for patients that suffer with this disease. The types of chronic cough we are studying are linked to 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 development of Haduvio and RCC.
As we have explained, with IPF as our lead indication and a specialty commercial sales model, we will develop Haduvio and RCC for patients which 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 one-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 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 data sets 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.
Lisa Delfini
Thank you, Jennifer, and good afternoon, everyone. The full financial results for the 3 and 12 months ended December 31, 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 31, 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 2 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 start-up 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.
Question and Answer Session
Operator
(Operator Instructions) Faisal Khurshid, Leerink Partners.
Faisal Khurshid
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 your estimation in the second half of the study, like this bolus that you talked about in December and January until you completed the enrollment? And then I have a follow-up. Thank you.
Jennifer Good
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 preplanned analysis and no upsize was required because you don't want to change the script they're using at the site. So no, we've been very careful to not have any changes in the second half of this population.
Faisal Khurshid
Got it. That's helpful. And I think before, you commented a little bit on the discontinuation rate that you were seeing earlier on in CORAL. Could you comment that -- now that you're almost done with the study dosing, how that's tracked in the back half of the study?
Jennifer Good
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.
Faisal Khurshid
Awesome. Thank you. Looking forward to the data.
Jennifer Good
Yeah. Thank you.
Operator
Mayank Mamtani, B. Riley.
Mayank Mamtani
Yes. Good afternoon. 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, multipart question, how might your baseline cough count differ from what you had in CANAL?
Jennifer Good
Yeah. So just first of all, the two-week placebo run-in, 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 just 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 placebo run-in. The powering assumptions around placebo, we had assumed 66% drug effect, 30% placebo or -- so 36% placebo-adjusted change. As you know, our SSRE confirmed that we're at least at that effect size or greater. So I think we were pretty conservative on our placebo effect.
We've seen generally across prior IPF cough studies, of which there's not a lot but the placebo effect is ranged between about 15% and 23%. 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 certainly not looking at that at my level, and I don't think Jim is either.
So I don't have any commentary around what baseline cough counts look. I do know that our inclusion criteria of how you get in and there's some minimum baseline costs that are required of VAS score didn't change. So I would assume that we should be roughly in the same range.
Mayank Mamtani
Thank you. And if I could maybe ask about the RIVER RCC data 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 the next three- to four-year time period?
Jennifer Good
Yeah. Thank you, Mayank. As we've said on commercially, we're looking at being -- treating basically patients that are treatment failure. 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 that layer of stuff. If a P2X3 does make it to the market, Glaxo have success -- and I hope for patients that they do -- I think we will look to -- you can try your P2X3 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 need still. I think as you know, the P2X3s have really only had success in the severe coughers and even then haven't shown efficacy in 40% of those. So there's a lot of people who are still seeking treatment.
And this moderate and severe somewhat an arbitrary line. I think the people that are really pursuing therapy not able to get treatment that helps them. I think they'll end up in trying our Haduvio.
Mayank Mamtani
Thank you.
Operator
Annabel Samimy, Stifel.
Annabel Samimy
Hi. Thanks for taking my questions. Just some more data and more questions around the data. Now that you've had about 10 days to mull it over, is there anything you can share with us regarding the efficacy that you saw max out of the 54-milligram dose?
And if this was similar to what you saw in the initial IPF trial, did you see a maxing out of that? And if you might still be considering 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 might indicate that you might see, potentially look at lower doses there.
And I say this, I guess, all with the AEs in mind and how that might be improved. Were these AEs based on initial treatment? Or do they come as they stepped up in dose? So I guess that's my first very long question.
Jennifer Good
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 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 clearly shows [ that peers ] 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 those.
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 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 effective dose early. So yes, we don't have more data.
When we do, we'll show some of that color. I probably got 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 our planning around that as well.
Annabel Samimy
Got it. And 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 you changing the inclusion criteria at all, given that you are positioning this for a third-line treatment after P2X3?
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?
Jennifer Good
No. So we'll -- in our inclusion criteria, it will be really similar to what we just did. There's got to be some minimum level of coughs. People have centered around this 8 to 10 coughs 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 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?
Annabel Samimy
No, it's pretty -- you pretty much covered it.
Jennifer Good
One of the points which slip my mind. But thank you, Annabel.
Annabel Samimy
Okay. Thanks a lot.
Operator
Leland Gershell, Oppenheimer.
Leland Gershell
Hey. Good afternoon, Jennifer and team. Thanks for taking the question. Wanted to just ask with respect to time lines. I know when we checked in last, which was before the RIVER readout. In addition to the efficacy data, you also need long-term exposure data to fill out the NDA package, which would impact initial approval time lines.
I'm just wondering if you are pursuing RCC in a Phase 3, and you also have, what I guess would be two Phase 3s for IPF cough, could that expedite your route to market because you may have additional safety exposure data from the patients who come from the late-stage RCC study? Thanks.
Jennifer Good
Yeah. That's a good question, Leland. So to date, 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 will be the NDA that we negotiate with the FDA about what safety database exposures they need.
RCC will be an FNDA. 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.
Leland Gershell
All right. Thanks for the color.
Jennifer Good
And I'm just going to follow up, Annabel. I remembered your second question, which was around treatment failures. And just to 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've 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.
Operator
Serge Belanger, Needham & Company.
Serge Belanger
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 RCC?
Jennifer Good
Yeah, it's a good question, Serge. So that study is screening, it's underway. There's been some, I would say, just operational logistics of sorting out certain things. It's a study nobody's done. So again, just typical Phase 1 stuff.
We have two good sites and have worked through that. Jim is back contemplating whether we need the 108-milligram dose in that study. So that's in the works now, I would say. We were dosing up through 108 milligram, but I think there's some thinking that maybe we won't need 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 and discuss our data and our path forward with the agency.
Serge Belanger
Thanks.
Jennifer Good
Thank you, Serge.
Operator
Ryan Deschner, Raymond James.
Ryan Deschner
Hi. Thanks for the question. What exploratory metrics do we expect to see at the time of the 3Q IPF cough readout, specifically thinking about exact question two or sleep cough frequency? And then I have a follow-up.
Jennifer Good
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 and some of the key secondaries, exact two will definitely be there because that's 1 of the key secondary studies in the endpoint as well as, I think, CSS. But beyond that, I don't know if we're getting any of the other secondary endpoints.
Ryan Deschner
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?
Jennifer Good
Yeah. 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. Yeah, 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. So we're not planning to stratify at all between moderate and severe.
Ryan Deschner
Got it. Looking forward to the 2Q readout.
Jennifer Good
Yeah. Thank you, Ryan.
Operator
Brandon Folkes, Rodman and Renshaw.
Brandon Folkes
Hi. Thanks for taking my questions. Maybe just 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 how the studies were designed? But just any scientific rationale we should think about when we see that data when we looking at the placebo adjusted? Thank you.
Jennifer Good
Yeah. It's -- I've gotten this question because the CANAL IPF placebo rate was actually a little higher than RCC, which feels counterintuitive. These crossover studies are generally pretty tight, so placebo doesn't usually rear its head up until the parallel arm design. I suspect it's because the RCC studies, everybody does these in the same 10 to 15 centers, high-end cough centers, really high-end thought leaders in the space. IPF is a little more out into normal IPF centers that are doing lots of studies.
So -- there 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 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.
Brandon Folkes
Great. Thanks very much for taking my questions and congrats on all the good data of late.
Jennifer Good
Yeah. Thank you, Brandon.
Operator
Kaveri Pohlman, Clear Street.
Hi. This is [Christian]. I'm on for Kaveri today. 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?
Jennifer Good
Yeah. 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 secondary's linked to your primary endpoint of objective cough. That seems to be centering around cough severity, which isn't quite the same thing as cough 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 these next studies and which metrics will be built in the secondary endpoints. But it will be a cross between the severity scales and then some of the quality of life metrics as well.
Got it. Thank you.
Jennifer Good
Thank you, Christian.
Operator
This concludes our question-and-answer session. I would like to turn the conference back over to Jennifer Good for any closing remarks.
Jennifer Good
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.
Operator
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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