Okay. Good morning, everyone, and welcome to the Trevi Therapeutics session. Happy to have Jennifer Good, CEO of Trevi, with us, as well as Dave Hastings, CFO. As you know, Trevi is now the solo operator in the chronic cough indication.
Who would have guessed, right?
Who would have guessed after all these years? It's a good position to be in. Jennifer, why don't you give us a quick overview, lay of the land, and then we can launch into questions.
Sounds good. First of all, Annabel, thanks to Stifel for hosting us. They've been a good longtime partner of ours at the company, and thank you for you guys for coming to our talk. Trevi is a simple company. We're a single-asset company that is focused in three different chronic cough indications: chronic cough and IPF, chronic cough and other interstitial lung diseases, and refractory chronic cough. I know some of you have followed this field for a while. They're very big unmet needs, and a lot of companies have come and gone through this space. I think we came into this space with sort of a different approach, which we'll probably talk a bit about, but we basically were treating cough through the brain as opposed to trying to treat it through the lungs solely.
I think with the benefit of hindsight, that's what at the end of the day, we're all alone in these three big market indications. We are in phase III in our lead indication. We've aligned with the FDA, and 2027 is a year with a lot of data ahead, so I'm excited about the future.
Fantastic. So, why don't we just get the SSRE out of the way? Because that's been a topic—
Haven't had that question before.
—has been a topic on everyone's mind. You went through it pretty well on your earnings call. But this is something that we expected this quarter, it slipped a little bit into next quarter. I think no big deal there. But maybe you can tell us how we should think about this and what the possible outcomes are, and why are people so suddenly nervous about—
Yeah.
—what didn't seem like an enormous catalyst to begin with?
First of all, SSRE stands for sample size re-estimation. It's similar to an interim analysis, except that we get no data. Essentially, what we're trying to do is make sure our powering assumptions are correct. We've used them in phase II. I mean, this is my fourth time using them. And it's really all about trying to just make sure that if your drug is working, you're going to get to the end of the trial with a statistically significant result.
We did this in our IPF program, and now what Annabel's referring to is in our refractory chronic cough program, which is in a phase IIb trial. We have an SSRE built in that when 50% of the patients complete, an unblinded statistician outside of Trevi will look at all the unblinded data and essentially confirm one of three outcomes. And we get no other information other than we've fallen into which bucket.
The first is you're at 80% power or better, so just continue the study as is with our original N. The second answer is you're in this, what they call conditional power range of 40%-80%. That basically tells us the drug is working, you just need to proportionally increase the sample size a bit. So it can go up to as high as an additional 52 patients.
That, as I remind people, that just means that either there was a little more variability, maybe your effect size was a little less than you assumed, but the drug is working and you should have a positive trial at the end. The third outcome is you're below our predefined definition of futile, which is 40%, and then we would get the futile answer. I think the reality at that point is your study's almost fully enrolled, so you probably finish it and look at the data.
I think to answer your drama question, Annabel, I think the reason it started getting so much attention is GlaxoSmithKline had acquired a company called BELLUS Health, which I'm sure some of you were aware of. They read out their two phase III trials this summer, both of which failed. I think the good news for Trevi, it's all bad news for patients, just to start with, but the good news for Trevi is there's now nobody left at all in cough. That was sort of the initial excitement.
I think the bad news as to why this became now more intensely focused is, it's been a really tough nut to crack in RCC. Glaxo didn't put out any of the data. People got nervous that maybe it's just too tough of a condition, placebo effect's a problem, et cetera. We'll just have to see what the data is. I think our approach is different. We feel good about where we're heading, and yeah, we'll get to that readout early in the first quarter.
Okay. Just to level set everyone, can you remind us what your placebo response was in your initial proof of concept study, what Glaxo's placebo response was, what your assumptions are for this phase II?
Yeah.
Exactly how variable this patient population actually is? So that's four questions in one there.
No, but that's the question because how their drug worked is somewhat irrelevant to us. That drug never had a big effect, and it was a peripheral-only agent, and they were trying to sort of thread the needle on cough counts. Really, the relevant question for our program is, what do we think an appropriate placebo level is in this patient group? It sort of started with Merck a few years ago, had a very high placebo rate in RCC trials.
From what I hear from all the KOLs, and I will answer your question specifically about numbers, but is that Glaxo was able to solve the placebo problem, that that placebo was not an issue in their trials. I think it's somewhere in this 25%-30% range. So it's higher than we see in IPF cough, but it's not a placebo rate that's sort of unsolvable. I think there's a lot of things of how they were able to do that. The biggest one probably being they made sure they truly got RCC patients in the study and not sort of other types of cough.
Annabel, you asked what our placebo rate was in our first trial. It's not so indicative here because that was a crossover design, if you remember. That tends to decrease variability, and we had a very low placebo rate of 9%. I think in our IPF trials, we had a placebo rate of about 18%-19%. Also probably not super indicative because I think the fibrosis is really, you tend to not get a big placebo response.
I think what I've told you I heard in these big Glaxo trials, it's somewhere between 25%-30%. Sort of long story short, that's all the numbers. We powered at a 30% effect size. In our phase II-A, we saw 56% effect size. We have taken into account that we think the placebo rate's going up, but that's some of what this SSRE will protect us against, that if placebo's a little more variable, we'll be protected in this conditional power range.
Okay, great. Then maybe you can talk about the max upsizing of 52 patients. Given that you're the only game in town now, how long do you think that would require to upsize, if in fact you have to upsize it?
I'm going to let Dave take this because he did a lot of work on money and time.
Yeah, I actually don't think it changes our guidance. The readout is second half of next year. Even in the max upsize scenario, we still think we can make that guidance. It'd be later in the year, obviously. The financial impact's minimal. It doesn't impact the runway.
Okay, great. How has enrollment been going given that there's obviously a patient population that's very much in need?
It's been strong. I've been really happy with enrollment. Annabel mentioned just full transparency. We had guided towards Q4 for this SSRE, but we had always told people it was going to be December. It's going to slip into January, so we gave guidance on our call that it's the early part of next year. We're talking about a few weeks. By the way, this was guidance we set for this trial, everything got off the ground. I'm pretty happy with enrollment. It's going strong. There's nobody else sort of competing for these patients.
I would also say, just when you watch the trial sort of top side from the dashboard level, activations have gone really well. All the sites are screening and enrolling. Discontinuations are low. Screen fails are low. It's a very high cough count coming into the trial. I feel really good about just the trial dynamics, sort of watching it from top side, which we're just kind of almost at 50% level. So feels really good where we're heading with the trial.
Okay, great. Switching over to IPF because you are trying to be more of a specialty cough company, and obviously IPF is a very high-need indication. You've put together a pretty comprehensive OCEAN program.
Yeah.
I like all your LAKE and OCEANs and rivers.
All our water.
All your water elements. It's great. Just describe the program. It's two, one goes out to 12 months, one is 24.
Yeah.
Why the different endpoints? What are the actual primary endpoint timelines for each of them? Just describe that, and then we can talk about the specifics around it.
Great. Our lead indication is chronic cough and IPF. Just to frame it quickly, about two-thirds of IPF patients have moderate to severe chronic cough, and we are tackling that part of the population. We had a nice alignment meeting at our end of phase II meeting with the FDA, and Annabel's right, we agreed on doing two studies.
The bigger OCEAN-1 study is a 52-week study. The efficacy endpoint is at 24 weeks. The 52 weeks gets us one year of safety data. The primary endpoint is a reduction in cough counts. That's the same endpoint we used in phase II, and our key secondary is a reduction in cough severity, also what we used in our phase II. I think the good news for us is it's really a nice replication of all the work we did in phase II, so it's truly confirmatory.
The second confirmatory trial is a 12-week efficacy endpoint. We did not have to go out and add on any more safety, so it's a 12-week endpoint. That's our OCEAN-2 trial. That's actually slightly smaller. It's 200 patients. I should have mentioned there's a slight difference. OCEAN-1 has 300 patients. OCEAN-2 has 200 patients.
The difference is in OCEAN-1, we powered through all seven secondary endpoints because we're trying to get a robust label. For OCEAN-2, we're only confirming the key primary and secondary endpoints. That is scheduled to read out second half of 2027, the smaller trial, OCEAN-2, and OCEAN-1 is scheduled to read out in the first half of 2028.
Okay, great. I guess two questions around this. The first one is, what gives you comfort that your durability can last from 12 weeks all the way out to 24?
Mm-hmm. Our phase II trial was six weeks. Really the only change as we move into pivotal trials, Annabel's asking the right question, is durability of efficacy. We're going from six weeks to 12 weeks to 24 weeks. What gives me confidence is, we also started off, when you first met us in our first life, we were working in pruritus. We got to phase III in prurigo nodularis, actually running parallel of cough and itch, and ended up pivoting to just focus on cough. But we did run a six-month trial in uremic pruritus and a 12-month trial in prurigo nodularis, and essentially saw no waning of drug effect.
In the two long-term trials we've run in derm conditions, which by the way, are also hypersensitivity, so similar. There's this whole sort of triangle of pain, cough, and itch, which are all very intertwined. We saw very good durability of effect of the drug. We've seen nothing that would lead us to believe that that should be any kind of issue here, but that is a question we're answering in these trials.
Okay, great. Then, I guess the second question around CORAL-1, which is a longer study. Can you go through these seven secondary endpoints and—
Ooh, you're going to test my memory.
—well, okay, just—
I'll tell you the important ones I can remember. The primary endpoint is reduction in cough frequency. Obviously, if you're a cougher, that matters. The key secondary is reduction in cough severity. How much you cough is one thing, but how severe your cough is another. We're measuring cough bouts. We're measuring breathlessness, which is a really important endpoint, because as you can imagine, when you're coughing, and on average, these patients cough 700- 1,000x a day, you get into these bouts for 10 minutes. You cannot catch your breath. You're constantly expelling air.
The two things IPF patients complain about is coughing and breathlessness. They're very intertwined. In our phase II study, we saw a statistically significant reduction in breathlessness as well. That would be an amazing label to get. That's important. The other one is a 30% reduction in your cough, because that's clinically meaningful. They're all then different cuts on sort of cough count.
Their sleep, is there like, or anything like that?
Oh, there's a quality of life measurement which encompasses sleep, physical pain, social embarrassment, things like that. Yeah.
But the breathlessness is the key component that you want in the label.
I mean, that gets a lot of attention because those are the two chief complaints.
Okay. And for the primary, which we all know is the 24-hour cough count, what is the placebo, what is the powering that you assume there?
Yeah. So, we assume there a 30% effect size as well. We saw in our phase II study, essentially under the same conditions, 35%-40% reduction or effect size. We think we've been appropriately conservative there.
Okay. All right, great. Can you just remind us also the enrollment criteria that you included in these trials? Was it a broad IPF population? Was it very How many patients did it exclude? What compromised populations do you have in there? Any of those questions would be great.
Yeah. It's pretty wide open, and that was part of our discussion with the FDA in March, that they really felt this drug should be accessible to anybody with IPF and cough. We had run a lot of the safety sort of studies that they cared about and drug-drug interactions. We had done some work around respiratory depression in people that had sleep-disordered breathing, that we got the all clear on that, so we were able to open up that piece of the enrollment criteria. We also had sorted out in phase II and then through drug-drug interactions that it didn't matter what antifibrotic you were on as background meds, whether it was OFEV, Esbriet, JASCAYD, which is a new launch. None of those affected the effect size of our drug and cough.
I think the only exclusion criteria are people that are very sick. There's a belief that they have less than a year to live because they couldn't get through the study, and they measure that through DLCO criteria and things like that. Or people that are on mu-agonist opioids because of our mu-antagonist mechanism, it would put them in opioid withdrawal. People either have to wash out of their opioid or just not enter the trial, but that's not so many patients. Anybody that was on an opioid was probably on it trying to mediate their cough, so I think they just wash out. It's not a lot of exclusion criteria in the study.
You do allow background meds, the antifibrotics?
We do. You can be on. Actually, in this trial, because we've sorted out all the DDI, you can come in on one background med, you can change your dose, you can switch to an antifibrotic, you can go off. Basically, we've concluded antifibrotics have no sort of issue. Doctors tell us all the time that they think about when an IPF patient comes in, how are they going to treat their IPF with an antifibrotic, and how are they going to treat their cough? I think we've been able to disassociate those two. Doctors have a lot of room to move on that.
Okay, great. As you mentioned, there is going to be another launch in IPF, a new drug that—
Oh, United Therapeutics?
Yes.
Or BI's JASCAYD?
I think it was BI's.
Yeah. They launched that drug. They're having a monster launch.
Right. How is that going to impact your market? Is that going to help you? Is that going to hurt you? What do you think? How do you think the dynamics play out?
I think broadly, there was no innovation in IPF for 15 years, then BI broke through with JASCAYD, nerandomilast. Then you've had United Therapeutics with treprostinil as well. I think getting some more innovation into antifibrotics, then BMS just had positive data as well. I think the belief is you'll have more patients better diagnosed with IPF, followed up, and I think that's just all good for our market size. Yeah, really, other than that, no impact. United Therapeutics is an interesting case because they actually have a cough problem because they have a device where they deliver it inhalation-wise. So, there's been some curiosity around whether our drug will make that more tolerable for patients because maybe you can settle down this cough reflex, but that's sort of a question to be answered in the future.
Okay, great. Then, maybe you could talk about the expansion into ILD. How do you see it differently? Do physicians see it differently? It does seem to be the same fibrotic disease.
Yeah. Yeah, so just to tie this together for people that aren't as familiar, IPF is an interstitial lung disease. It's just the most terminal, the most severe, and the biggest patient group. The rest of the ILDs is a collection of lots of different comorbid conditions, lupus, RA. I think what they all have in common, whether it's IPF or these other 200 other interstitial lung diseases, is fibrosis in the lungs. That's sort of the hallmark of interstitial lung diseases. For our patient group, they have cough. For any of you that have followed the IPF landscape, or the antifibrotic landscape, people often go from IPF, the drug developers, into what's called PPF, which is a progressive phenotype. We don't need this progressive phenotype because we're not measuring FVC changes. We just need cough.
If you have basically lung fibrosis and cough, you are our patient. Annabel's right. We just recently met with the FDA in October to say, "Okay, we've aligned with you on our IPF cough program. How now can we pull in the rest of these interstitial lung disease patients?" The agreement that we have with the agency is we'll do some phase II work, confirm that we're in the same dose range, and then we believe as long as our IPF program is positive, that we'll only have to do one ILD study. We'll be able to file an sNDA and essentially double that market opportunity. We have a pretty clear path with the agency.
I have to say, this division's been really helpful and collaborative. They're super interested in cough, and they know that it's been a tough area for companies. We have found them to be very accessible, very collaborative, giving us very good comments. I feel pretty encouraged about the path we're on there.
Can you remind us of the dosing in the IPF trial versus what you're looking at in the ILD trial?
Yes. In IPF, we did a dose range of 27, 54, 108, concluded 108. We didn't need it. It was too much. 27 was minimally effective. We're moving forward in IPF of a titration dose of 27, with the fixed dose being 54 milligrams. These are all BID. I'm going to add one other piece to this you didn't ask about, Annabel, which is refractory chronic cough appears to need lower doses. We are actually studying lower doses there. We are doing 27 QD, 27 BID, and 54 BID. The conversation that we had with the agency, because ILD patients are not as terminal and sick as IPF patients.
The question the FDA had, which was a fair question, was, "Is your dosing going to look more like RCC patients, or is it going to look more like IPF patients?" That is an answer we do not know. It is why we are doing some dose ranging, because there was a discussion of, "Can we just go straight to phase III with our IPF dosing?" We are going to study in ILD 27 twice a day, 54 twice a day. We have not seen a need to have the higher dose, so we just left that behind. If for some reason it appears that ILD looks, at the end of this, a little more like RCC, we would probably just throw in a lower dose in phase III. That is the plan.
Okay, so you are not looking at the lower dose yet?
We are not, because we think the hypothesis here is these are all the same patients. They have fibrotic lungs and they have cough. The hypothesis is you are going to have the same doses. But if for some reason it looks like you need lower doses, we will just throw a lower dose in phase III as well.
Otherwise, it looks pretty much like the CORAL study did.
Yeah, exactly.
Exactly the same.
The only difference is, Annabel, if you remember, CORAL was six weeks of fixed dose.
Yes, this is 12.
We are doing 12, because it is clear that FDA wants one 12-week study in cough, and they want one 24-week study in cough. We decided to just serve up the 12 weeks here.
Okay, great. I just want to go back to the issue of the lower doses, because that could potentially give you an opportunity for brand splitting. Can you walk through the mechanics of that, and how low could you potentially go? Exactly what kind of dose do you need to have to create a true brand splitting type of opportunity?
Yep. There's a couple answers to that question. Technically, this is a very hard drug to deliver at low doses. It's got super low oral bioavailability, like 15%. Currently, the lowest dose formulation we had was 27 BID. That's why it's always been our lowest dose we've looked at. Because of our RCC data, we're anticipating that we could end up needing lower doses in this indication, which to Annabel's point, could prove to be quite beneficial, because you could end up in a place where you can either brand split or price off a per milligram basis and maybe preserve that anyway.
In parallel to running our phase II-B, we have done a lot of work on much lower doses, BID, QD, trying to figure out at what point does this tablet just fall apart and you can't do extended release, which there is going to be a point where we find that. We think we've found that now. Long-winded answer to what we're going to look at when we get our phase II-B LAKE data is we're going to look at what does it appear is the optimal dose for a patient, and then we've done all our technical formulation work to figure out how low do we think we can actually go to formulate this drug, and then we'll try to make good decisions about how we marry that up in the next study.
Okay, great. Maybe we can talk a little bit about going it alone with a specialized indication. It seems that you're capable of doing the specialized aspect of it. Maybe talk about that, and then if you have the high-class problem of RCC hitting, then what?
Yeah. It's a good question. We've built Trevi, and this is sort of a— We were thoughtful from the beginning about picking indications that we could take to market ourselves. I think big pharma commercializes very well. I think this is an obvious target for big pharma. It's a big indication in hitting in 2029. But I think building a company in the hopes that big pharma, you align with their strategy at any single moment's a bad strategy. We have targeted indications that we can build a sales force. It's respiratory, it's 50- 100 reps, it's high pricing. We can definitely do that ourselves. I think Annabel's right. That is super clear for IPF and ILD. These are all seen through 90 ILD care centers in the U.S., so it's very achievable.
If you followed Insmed, if you followed Verona, those were very successful launches in this space. RCC complicates that a bit because it is two million to three million patients and it is much more primary care. We have said very clearly that if Trevi launches an RCC, we are going to target the most refractory patients seen by pulmonologists that have failed at least two other treatments. Our goal is not to get two million to three million patients, it is to be sort of the drug for the most refractory patients because we are going to charge the price that we think we can charge in IPF, which is around $100,000.
I remind people that we only need to get 20,000 patients to have a $2 billion drug in RCC. We will remain a specialty-focused company with pulmonology as our call point.
I think that is the exciting part of the story. I mean, with $2 billion verticals in each indication, that adds up quickly, right?
Yeah.
That is how I was able to recruit you in, right?
That is exactly right.
Dave thought he was retiring and I said, "Let me show you these numbers." And he said, "All right, fine. Sign me up.
Very, very excited.
Can you just tell us what percent of patients for RCC, the refractory patients, are actually seeing the pulmonologist?
Yeah, 40%.
40%. It is actually quite—
It is big.
It is 40% of phase III volume.
That is still 650,000 to one million patients. It is our target focus.
Uh-huh. You still think that it could be about a $100,000 drug even in that population?
Yeah. There's going to be a point now, and we always point out, DUPIXENT did that well. They started off in specialty indications and then got to bigger. You can handle some of that through rebating, although to your question earlier, this is where if we got into lower doses and could just get into a whole different pricing corridor would be helpful. We'll sort that out as we go. We'll sort of optimize the commercial landscape.
I know that you built this company to depend on yourselves for marketing, but obviously—
Independent women.
Exactly. This is a big indication. With a number of these large pharma companies still trying to tap into the IPF market, maybe with the antifibrotic approach, what is the level of interest that you're still getting for what's considered a more symptomatic condition of IPF rather than treating an underlying disease?
I mean, interest is high. I spend a lot of my time these days making sure that people that should know us, know us, and I know people at the right levels. I think we'll just make a decision for our shareholders. Are we better off to launch this ourselves or is there a big enough check on the table should that day come?
I mean, the one thing I would say is that I think we're well-positioned to complete the phase III studies, right? I think given what happened in RCC, it's probably a likely outcome. We'll take that on our own, at least through that data point.
But that would require them to actually see the data in RCC first.
Yeah.
Because I don't think they want to take the risk that Glaxo did at this point.
I do think you're right. I mean, I've made this comment. I think post two failures in phase III, I think companies are going to want to see our phase III data, and then basically they're only buying commercial risk at that point. And that's great for us. I mean, we are well underway on these trials. We have the capital to do it. I think it's a great value inflection point for investors.
Can you remind us who the players were in RCC that were initially interested in this market?
I mean, it was broad. I mean, Glaxo, Merck, Bayer, Shionogi, Amgen, Roche. I mean, there's been a lot of people trying to crack this nut along the way. BI.
Have any of them moved away from this indication at all or pulmonary indications at all, or are they still in it?
Some, like Roche, got to be more of an oncology company when Esbriet went generic. But no, for the most part, a lot of them are still hanging around. And you guys know what's going on in big pharma with their patent cliffs. I mean, this is a potentially $6 billion-$8 billion drug that will launch its first indication late 2029. There's only so many of those around.
Yeah. Well, clock's ticking on that one.
Yeah.
Can you just remind us again your cash position, what it gets you through, and can you do any kind of pre-commercialization activity? Can you build any commercial infrastructure with that level of cash?
Yeah, so we're well-capitalized, $299 million in cash, no debt, very clean balance sheet. That really gets us the key clinical inflection points, gets us IPF through approval, and gets the two phase II studies done in ILD and RCC, and also funds some pre-commercial activities. We didn't really contemplate funding the full commercial launch with this latest round of financing, but we have plenty of time to do that, and there's a lot of interesting structures the company will have access to when that time comes.
Will you have any ability to start a phase III for ILD to potentially roll it into—
Absolutely.
—similar filing for—
Absolutely.
—for IPF? Can you just tell us the mechanics of that again? You get the phase II data, design the phase III, and then look for a label expansion at the same time?
Yeah. The current plan is, and this is what we discussed with FDA, we will get our phase II data. We will have by then our OCEAN-1 or OCEAN-2 data, the 12-week data for sure. Hopefully OCEAN-2, I am sorry, I am mixing up my OCEANs. OCEAN-1 data is going to be close to being finished there too. I think in a perfect world, we would love to go back to the FDA with all of our safety data out of OCEAN. I think that will give us the optimal position to do very little safety data in ILD. But wherever we are, we will do a data cut, and then we will discuss what phase III has to look like. We will go back to FDA and then launch into our phase III.
All right. That begs the question, in the event that IPF both are very successful and ILD is successful, is there a scenario where you do not do a phase III and it just gets a broader label for ILDs? ILD, IPF being one of the ILDs.
Obviously, we will go back and talk to the FDA. That is all data-driven. I do not want to guide towards that because I think of ILD as an sNDA and that we are going to need a phase III study. But that phase III study is going to probably be 200- 300 patients for six months. So it is not going to be super onerous.
Nice and fancy.
Yeah, but we'll see. It's all data-dependent here.
Okay. Remind us when that ILD study reads out again.
First half 2028.
Okay. All right. It all happens at the same time.
It's a lot of action in 2027 and 2028.
Okay. Well, I better stick around then.
Yeah, you're not going anywhere.
I've been around for this long, so I might as well. All right, that's all we have time for. Thank you.
Thank you, Annabel.