Trevi Therapeutics, Inc. (TRVI) Earnings Call Transcript & Summary

All right. Good afternoon, everyone. Thanks for being here. We're very excited to have Jennifer and James from Trevi here with us for this session of Morgan Stanley Global Healthcare Conference. I'm just going to go through a quick disclosure. For important disclosures, please visit www.morganstanley.com/researchdisclosures with any questions, contact your institutional salesperson. I'm Judah Frommer, one of the Smid biotech analyst here. And like I said, we're very excited to have Trevi with us for this session. So maybe we'll start off. It's been a year of significant progress for Trevi before we dive in -- maybe give the audience and in short of the company and your chronic cough programs from a high level?

Sure. First of all, thank you for having us. We appreciate it. And thank you for those of you that have hung around till the end of the day to hear us. So Trevi is a simple story. We're a single asset company focused in chronic off indications. Three indications, idiopathic pulmonary fibrosis cough, other interstitial lung disease cough and refractory chronic cough. There's been a lot of sort of movement on the competitive landscape around that. We have aligned with the FDA on our path forward and our lead indication of IPF cough -- we've started those trials. We can get into more detail. So we are in Phase III, looking for a lot of data to start reading out some later this year and then second half of next year. So it's been an exciting time to be in it. I'm joined by Jim Cassella, who's our Chief Development Officer. So he's had a very busy summer sort of getting all this off the ground.

Great. And before we jump into the asset, maybe let's start with unmet need in chronic cough get is situated on the epidemiology, how patients are managed currently and what the potential opportunity is here for trade .

Yes. So chronic cough has been an area that big pharma has been interested for a while, very big markets. So just to orient you, just to kind of take each of the slices. Idiopathic pulmonary fibrosis has about 140,000 prevalence of about 140,000. 85% of them have cough. So 2/3 of them have uncontrolled coughs. So you can think about 100,000 patients -- it's 1 of the #1 complaints of these patients. So we all know there's been a lot of work in IPF. Those are antifibrotics, slowing down disease I think what our program brings to these patients is actually helping to manage their quality of life and day-to-day living. The other interstitial lung diseases, ITM is an interstitial lung disease, it's about half that market, you essentially double that whole opportunity. So a lot of leverage in that market overall with probably an additional clinical trial. Refractory chronic cough is a very big opportunity. That's sort of 2 million to 3 million patients a little bit blows up the specialty model we're in. But the reality is there's been, I think, 20 drugs tried in RCC, all of which have failed, and we should probably talk a little bit about why we think we're different. But we are approaching that market. We're not going to change our specialty sort of focus there. We're going to go after the most refractory patients and maintain our pricing there. So each of these indications is quite large. And as I mentioned upfront, we're alone left in these cough indications. So really exciting commercially. Final point on that is maybe you're going to get to this later, but this -- respiratory has been an area very manageable commercial-wise by biotech. We're excited about the situation we're in.

Okay. Great. And we'll get into refractory require call specifically. But maybe just starting with some history around now, how is it differentiated from other cough mechanisms that have been explored?

Yes. And that's sort of the cracks that when we got into this space, there was probably 20 programs going on. And most of the programs dealing with cough through peripheral mechanisms in the lung, which sort of makes intuitive sense. I'm 1 of the 2 co-founders of the company and my co-founders a neurologist, and he had been sort of coveting at me for a while that cough -- neurological cough is not a lung problem, it's a brain problem. It's a response to -- if you think about IPF, it's essentially fibrosis of the lungs and your brain sending this signal, acknowledging this fibrosis. And so Tom was convinced that whatever drug you treated this with it had to be neurologically active. So -- what's interesting about our mechanism, we work peripherally in the lung, but we also work centrally in the brain. So along that whole cough reflex arc. And I think as our data is rolled out, it's had a very big effect in almost every 1 piece to come on early. So I think over time, these other mechanisms have failed were sort of flat. And I think what we all take away from that is managing cough centrally is important.

Okay. And I guess within the context of opioids, how does abuse potential compare to other opioids? How well has that been characterized? And we'll get a question out of way upfront that typically we'd save until later, but potential for scheduling risk in your mind.

Yes. And I'll touch on it, Jim, you add any color. I know you're going to get into a lot of trials, so you'll be chat for a while. So nalbuphine is an opioid. But as I like to explain to people, not all opioids are the same. There's 4 opioid receptors. When people hear the word opioid, they think of morphine, fentanyl. Those are all new agonists -- there's a class of drugs that are called mixed agonist antagonists that were designed to get away from drug addiction. So our drug nalbuphine actually blocks that new receptor and works at Capa. So the experiment we were running is Capa helpful. And so that's kind of where we started off. The drug has been around as a subcu injection for decades. So it's been unscheduled. We had to do some work. We did some human abuse potential work. We've done some respiratory depression work. All of that's been clean. We believe this drug is going to stay on schedule. So we picked this drug intentionally because we thought we could get away from a lot of the baggage that is plagued opioids.

Okay. Great. And you mentioned that it's an older drug. So just on patents and IP more generally, you've been proactive on patent strategy. Maybe talk a bit about the protection for Haduvio? Is there anything we should be looking out for on this front going forward as well?

Yes. So it's an old drug. So no composition of matter. We have method of use patent issued that's quite broad in our IPF COP program. basically covers chronic cough and IPF with nalbuphine. So broad claims. We have spent a lot of time and energy in the company over the last sort of year filing additional claims around the label, a lot of work that's clinical work that's been done continue to expand that issued patent goes through 2039. So we'll have a good 10 years of protection. What we're now trying to do is build around the label and extend that out to '46, '47. So a lot of room to move here. There hasn't been a lot of work done in cash. There was a lot of known. So we feel we've got a lot of opportunity to patent.

Okay. Great. And maybe just transitioning to your lead indication, like you said, IPF-related chronic crop. At a high level, maybe help summarize the data we've seen thus far, safety and efficacy from the Phase II studies and maybe loop in, you had a presence at ERS recently. So what were key takeaways there as well.

Sure. So we have good experience with our IPF population. We've run 2 studies to date. -- that were enabling us to start the Phase III program. First was a crossover study of the CANAL study. We learned a lot from that study. We did some dose ranging. The real important study that we ran was the CORAL study, which we reported out. This was a parallel arm study. We did some dose exploration in there. We were able to really determine our effect size, we were able to figure out the best optimal dose bring forward. So what that did for us is we picked the 54-milligram twice daily dose. We brought that to the FDA, had a discussion with them about our dose ranging about the efficacy that we saw there. So in our CORAL study, we did see about a 36% differential from the placebo control arm. We saw optimal dosing there. We had a 108-milligram twice daily dose that was also included in that trial, but the 54-milligram dose was really the sweet spot dose. So we saw really, the optimal efficacy. We saw no additional benefit from the 108-milligram dose, so it was easy to make the decision to bring that forward. And I think on the safety side, what we saw was a very well-behaved and well-characterized safety profile that we've seen in -- throughout our cough program, but also with the history of the drug that existed before we even got into the cough space. So we see typically CNS and GI type side effects. These are typically transient. These are typically mild in severity. And I think that was the package that we brought to the FDA to get us to the end of Phase II meeting and into the Phase III program.

Okay. So maybe just getting into the Phase III, maybe let's talk a bit about design of these studies, and you've initiated the first study. Any update on status of the second study as well?

So the design really follows from the CORAL study. That was a really important study in a number of different dimensions. But it had a 2-week titration period, and a 4-week fixed-dose period. So what we brought forward was the 54-milligram dose versus placebo. Now we're looking at a longer duration trial with the same primary endpoint, which is 24-hour objective cough monitoring. We did exploration and confirmation of PRO data from the CORAL study. We brought that into the Phase III program. So the end of Phase II meeting was a really great meeting for us and that we got agreement with the FDA that we were looking at our primary endpoint, the same as what we saw in the CORAL study and the secondary end points that we wanted to bring forward on the PRO side. They agreed that those were important endpoints to bring forward. The differentiation now is really where we see the duration of the trial, what the FDA is looking for in terms of long-term safety and what they're looking for in terms of showing durability of effect in terms of efficacy. So with that, we are running as our OCEAN 1 study, our long-duration study, 52 weeks of placebo-controlled safety data with our primary efficacy endpoint at 24 weeks of fixed dosing. So with a 2-week titration than 24 weeks of fixed dosing. So that's where we'll get our primary efficacy read with 52 weeks of long safety data. Our OCEAN 2 trial, just to sort of fill in what we came out of the end of Phase II meeting with is really a confirmatory on the efficacy end point where the FDA was not as strict in terms of looking at the duration of the trial. We came through an agreement that a 12-week primary efficacy endpoint for the OCEAN II trial would be sufficient for showing confirmation of the effect on cough. And we're powering that trial for our primary efficacy endpoint as well as our key secondary endpoint. The OCEAN 1 trial, which is the longer duration trial, we have a number of key secondary endpoints, and we're powered. That's a 300-patient trial. We're powered for all the key secondary end points. With OCEAN 2, the shorter duration trial, we are powered for the key secondary and the primary endpoint. That's a 200-patient trial. So that comprises the bulk of the data we need for efficacy and long-term safety.

And timing, Judah, you asked about running, OCEAN will start this quarter.

Yes. Okay. So great. And then maybe just back to dosing in the Phase III, like you said, you tested the in Phase II. I guess maybe just a little more detail on the 54 mg dose selection. What do you see at 108 that convince you that 54% is the right dose? Or was 54 just good now.

So what we saw was a modest increase in the effect on cough frequency through the cough monitor with the 108 dose. But as we looked at very important parameters on the patient reported outcome side, the secondary end points, when we look at things like patient reported cough severity, patient reported cough frequency, we saw no added benefit with the 108 dose. So just in terms of risk benefit, we saw the highest benefit really when you look at all the data together with the 54-milligram dose with no added benefit from the 108.

Okay. Great. And then maybe just a little more color on the titration strategy for the Phase III, you've characterized the AEs with early transient, mostly mild. So what have you learned from prior studies that helped you to optimize the titration here?

So we did a really careful analysis of the adverse events that occurred both in our River program in the RCC space and also in the IPF space. And one of the things that is true across both patient population is that we have the very similar type of adverse events, CNS and GI in nature. And what we see is in those 2 very different populations, we see the same type of adverse event profile. But importantly, what we see in the analysis of when do those adverse events come on, they come on early, they come on with the initial dosing with in titration, the 27-milligram dose. And we also see a very similar duration of the adverse events, the CNS and GI, slightly varying between some of the specific adverse events of interest. So what we saw there was a characteristic sort of shorter duration usually coming on with the onset of dosing. So what we did for the Phase III program in IPF is we increased our titration period where we look at QD dosing with the 27-milligram dose. We did that before, and we started off with that in the CORAL study. But instead of a couple of days, we made it a week of QD dosing. The idea there being that maybe we can mitigate some of these adverse events of CNS and even some of the nausea and potentially vomiting with nighttime QD dosing for 1 week, we mitigate those. And then we go into a 27-week -- 27 mg BID for another week. So that came out of our analysis of the onset of the adverse events and sort of the nature of the duration of these things. So we think the titration is going to be very useful in mitigating some of the effects that we saw even in CORAL, some of the effects that we saw in RIVER where we can maybe get rid of some of those effects while the patients are sleeping.

Okay. Great. And like you said, OCEAN One, evaluating the primary endpoint at 24 weeks and 12 weeks for Ocean 2. The Phase Ib CORAL, you evaluated at 4 weeks of fixed dosing there. So talk to us a little bit about confidence that cough reductions you observed at that 4-week time point will translate to longer time points. Any data with nalbuphine or the mechanism that kind of adds comfort on this?

Yes. So I think there's 2 ways to look at that. We have data from our previous trials when we were looking in, where we had run a study that was a year long. And in that, we saw full maintenance of effect. So no loss of the durability of the response. So we have data with itch. There's previous data that was captured in pain. So I think underlying these things that these are mechanisms or indications that have maybe a common underlying mechanism that leads to this concept of sensitization. We have not seen empirical data that suggested that we would see any kind of loss of durability of response or tachyphylaxis in that time period. Also, I think there is a possibility that the antagonism that we have inherent with our pharmacology different than the mu agonism that you see with the morphines in the fentanyls of the world. I think that switch from agonism to antagonism mechanistically can help prevent that can occur at the receptor level as well. So -- but I think the empirical data with our itch studies tell us that there can be some confidence there. Of course, the data will be coming out of the OCEAN 1 study primarily, which is our longest study where -- but we don't expect to see any kind of tachyphylaxis.

Okay. That's helpful. And then maybe just touching on some operational aspects of the study. First, on the objective cough monitor that you're using, you've leveraged it in prior studies. There's some regulatory history with that device. So maybe for those who aren't as familiar, give us a little bit on how the device works and how it was validated.

So we can thank Merck for a lot of the heavy lifting on the validation of that. I may learn the hard way that they needed to do a little bit more validation work with the studies. They did all that work. I think, the company benefited. And I think as an industry, we benefited from all the analysis and from the hard work that was put in there. that sets the stage for us where some things were learned during the whole Merck program. Now in our case, we did work out an agreement with the FDA that once we did the CORAL study, as others have to do, there's a validation study that goes on after the fact. And actually, we reported out the results of our validation study when we had our Investor Day. And what we showed there was that when you look at the compression algorithm that is used specifically for the system where they have human readers, and they actually score. It's a chest sensor which picks up acoustic signal, and there's also on audio monitor, they're scored. They can -- the readers can hear the cough they count them in a compressed algorithm. So we had to validate the algorithm from the uncompressed to the compress. I think that was 1 of the initial issues. We showed that there was extremely high reliability going from the uncompressed to be compressed. And also, the inter-rater reliability. These are people that are highly trained to listen for cough sounds and count them. and we did inter-rater reliability with 3 different raters, and we had very, very high relationship, high correlations between each of the 3 raters. So in the world of validation, we feel very comfortable that this was adequate and sufficient to satisfy the needs that we have in the IPF program. Further enhance the validation that was done previously by other companies. So we feel very comfortable. It's a very different kind of experience now with Vitala Graft system versus the early days when there were some issues around that.

Okay. Some good background. And then maybe just talk about site selection for the Phase III program a bit. How many of these sites do you have experience with? And how many have participated in other Phase III programs.

So I think we had a great experience with our CORAL study. We have a lot of those sites that are still involved and the beauty of what we're doing here in the U.S. is that we're working with the -- a lot of the specialty centers that are part of the pulmonary fibrosis foundation network. There's 80 to 90 sites there. We have tapped into a vast majority of those sites between OCEAN and OCEAN 2. That's where the bulk of ILD patients, IPF and non-IPF patients go for their care. So we really are tapping into centers that have the patients well-characterized patients, and a lot of those centers have cough experience.

Okay. Great. And we should have done this earlier on, but maybe we characterize kind of standard of care for IPF clock. There are some off-label treatments, there are no approved therapies. And with that in mind, how do we think about clinically meaningful outcome on the primary endpoint in Phase III? And while we're there, maybe help us with assumptions around power.

Yes. That's a good question. We can take this a bit if you want, Jim. It's the standard of care. They try all the things you try when you have a long viral cold, are up they'll try some. None of it really works. It's been a frustrating aspect of the disease. There's been publications put out that 30% reduction in cough is clinically meaningful. We've also had patient boards where we've consistently heard any level of cough reduction is helpful to me. I think the real answer here from our trial perspective is we did a lot of work about what's important to patients and their patient-reported outcomes. And frequency is definitely important, but cough severity is equally important to them. So how severe they cough. And so that's our key secondary endpoint. We've been hitting our primary and reducing cough and then reducing cough severity is clearly clinically meaningful. As far as powering and happy just but at a high level, we've assumed a 30% effect size on reduction in objective cough. In our Phase IIb trial, we saw a 36% reduction. So I think we've been appropriately conservative here. So we felt about that.