Hi, good afternoon, and welcome to Needham's 23rd Annual Healthcare Conference. Happy to have the Trevi Therapeutics team with us for our next session. They are developing novel therapies for various chronic cough disorders. And with us, we have the company's CFO, Lisa Delfini, the Chief Commercial Officer, Farrell Simon, as well as the President and CEO of the company, Jennifer Good. So I'll hand it over to Jennifer, so she can give us an overview. For those listening in online, you can submit questions via the portal that you are listening or watching on, and we will take those as they come in. So, Jennifer?
Great.
Take it over.
Thank you, Serge. No, thank you for having us. Needham's been a longtime partner of Trevi since our IPO, and so we appreciate you guys including us in your conference. Trevi is a clinical development company. We are focused in chronic cough indications. We have two lead indications, chronic cough and idiopathic pulmonary fibrosis and refractory chronic cough. We think because of our mechanism, which is a little bit different, it's got a dual mechanism, not only peripherally active in the lung, but also centrally active in the brain, we think we have an ability to work broadly across cough conditions and potentially have the best data. So we're excited about that. We have an exciting 12 months ahead of us. We've got a lot of data, data readouts coming, which I'm sure we'll talk more about.
I won't steal Lisa's thunder, but we're a well-funded little company, so we haven't had to worry about trying to raise money over the past couple of years. We've had our heads down, working on clinical development.
Great. So maybe let's start talking about nalbuphine. I think it's a molecule that you've had some experience with over the years. Maybe just tell us a little bit about, you know, the molecule and its mechanism of action, and how it differs from other opioids in its scheduling.
Yeah, happy to do that. So Serge is right. I've actually worked on this compound over two companies. I previously ran a small company called Penwest Pharmaceuticals. We had started developing nalbuphine there. It was broadly in the opioid class of drugs but did not have the likability and baggage around scheduling that, morphine, fentanyl, all the Schedule II opioids had. The problem with that class of drugs, these mixed agonist-antagonists, is, they weren't available in a very, good delivery form for chronic dosing. They were all subQ injections or inhalations. And so what we did at our prior company was formulate it into a nice twice, Our prior company was acquired by our strategic partner.
Tom, my neurologist Co-Founder, and I went back down and bought this compound out and started Trevi around it, and it was really because, super interesting compound, had efficacy associated with it, the class has good safety affiliated with it, and the drug was unscheduled by the DEA, and we can delve into that more. But, those were the things that sort of drew Tom and I in, and I have to say, the drug has worked in every indication we've studied it in. So we've decided in 2022 to really bear down and cough and try to get these over the finish line.
Yeah, and your first trial in cough was very successful, very good, positive results. Maybe just talk about why IPF cough as an initial indication, as kind of a, maybe even a proof of concept for a broader cough role?
Yeah, it's a good question, Serge, 'cause when Tom and I started looking at cough, you know, the experts were really pushing everyone towards refractory chronic cough. There had been a compound in RCC, gefapixant, the Merck drug, which had been studied in IPF cough and had failed, and so there was sort of this wisdom that it was too hard of a patient population. It's a progressive disease, end-of-life disease, and it was too hard to move the needle here. Tom was really adamant, being a neurologist, that this was the right proof of concept, to use your words, because the belief was because of the fibrosis that was going on in the lungs, it was sending a signal up to the brain stem that something was wrong. And the brain stem can react in a couple of ways, one of which is coughing.
So 85% of these patients cough, and so Tom was really sort of locked in on if our drug's working as we think it is, sort of centrally in the brain. This was the right experiment to do. And you are right, I think. Talk probably more about our data, but not only was it a big effect, it worked in everybody but one person in the trial. So I think certainly validates the pathway.
Yeah. And, I'm sorry, the proof of concept was, I think, a very simple protocol. I mean, simple in the sense for a proof of concept trial, but, maybe just talk about how quickly you were able to enroll and, the results that were achieved.
Yeah, so it's a phase II-A crossover design, so parallel or a crossover design, placebo-controlled. It's the same study that's been done in virtually all the cough studies, in either refractory chronic cough or IPF cough. Sort of crossover designs have pros and cons. Certainly, one of the pros is you're your own control, so you get a lot of power out of a low number of subjects. So we had about 40 subjects in the trial. And to your question about how quickly you could enroll, it was a tricky... Everyone, you know, everybody running trials during this time will appreciate, it's a tricky benchmark 'cause we started it right at the end of 2019 and then ran into COVID. And so this is a, you know, pulmonology-impaired patient group, who are quite sick, and there were lockdowns going on.
We were running this partially... o r in the U.K., the government had a lockdown. Patients couldn't leave their house and go places. So I would say it bumped along pretty slowly until we got to the fall of 2020, and then it moved along, and we were able to get the study enrolled and reported out.
Okay. And if I remember, you had over 50%, well, yeah, over 50%, placebo-adjusted cough reduction.
Yes.
The onset of action came on pretty quickly, even during the titration phase. Maybe how that, you know, expanded your thinking towards the phase III development of the drug?
Yeah. Yeah, so the basic design was a dose escalation trial. So people started off at the lowest dose, 27 mg, went to 54 mg, went to 108 mg, and 162 mg over the course of three weeks. You are right, we saw a big effect on the primary endpoint, which was an objective cough monitor, which has been a high bar for some to actually get through. We saw a 76% drug reduction, 22.5% placebo. So for the 52.5% placebo-adjusted change, I think importantly, all the secondary endpoints also lined up with that. So they were all statistically significant as well. From the patient-reported outcomes, we were able to see that this drug started working very quickly.
By day three, it was actually statistically significant, which was still on the 27 mg, just crossing over to the 54. When you look at the data, you also see that by the time you get to the high dose, it doesn't appear you're getting much incremental benefit. So as we moved into our next trial, which is a parallel arm dose-ranging study, we've dropped the highest dose, and we're studying our three lower doses, 27 mg, 54 mg, 108 mg, really trying to zero in on the optimal doses to take forward into the pivotal study.
Okay.
Same primary endpoint, the objective cough monitor, and pretty similar secondary endpoints as well.
Yeah. And I think this is a drug that has... I mean, it's a mixed opioid, so you do need to titrate it, to maximize or enhance the tolerability.
Mm-hmm.
So how should we think about that titration? Well, I guess, how was it in the phase II trial, and how is it modified, going into this phase II-B dose-ranging trial?
It's a little slower in this trial, mostly just for logistics. I think every week you titrate up, but it's kind of interesting 'cause the parallel arm design, if you're on the 27 mg, you actually never titrate up, you just stay on that dose. The 54n mg, you only do one step up, and then the 108 mg, it's basically at the end of each week, you go up. The phase II-A data that we just discussed was a little quicker. It was every three-four days you were moving up in the titration.
Okay. You've had the data now, I guess, for close to two years. So, I'm sure you've had a chance to present it at medical meetings, maybe just kind of the KOL feedback you've gotten since then.
Yeah. So we got it late 2022, and have presented it at multiple meetings and done market research, and I'm gonna let Farrell actually speak to that, just so you don't have to listen to my voice this whole call.
Thanks, Jennifer. Nice to see you, Serge.
Yeah.
You know, as we look at KOL feedback, it really comes across, I think, as in a multitude of areas. One is just the robustness of the data, and we've looked at this in multiple ways. Those that are on anti-fibrotic, those that are off anti-fibrotic, which are the standard of care within this disease state of IPF, and the results were consistent throughout. I think what we also looked at is different levels of cough count. The low-the moderate coughers, the high-frequency coughers, it held up in that area as well. And I think we'll have some very interesting presentations coming up at ATS as well about cough bouts, which will be presented by Jacky Smith, which is very great about just looking at what that impact is on cough.
So we've looked at this a number of ways, and in market research, as Jennifer mentioned, one of the things that we really looked at was where does this fit within the place of therapy? How do doctors perceive this? An interesting anecdote came from one of the physicians: as they initiate IPF patients on therapy, antifibrotic can sometimes be difficult because the patient doesn't feel any benefit. But one of the doctors says, "You know what?
I would actually start them on a cough therapy like this initially, especially with the quick onset of action, because you're gonna see a benefit of that cough therapy, and you're gonna get a quick win with the patient before I can initiate them on anti-fibrotic therapy." So it's not to replace the anti-fibrotics, but I think there's a lot of flexibility when you look at how physicians could use this in IPF patients.
Okay. And do you think those physicians think nalbuphine can impact the disease progression or the actual coughing pathology here?
So I'd say I think they're split, right? I think we'd have to produce data for that, but there's a lot of registry data that does support that hypothesis. So there is a large registry that does support an increase in cough severity, measured via a scale called, you know, an LCQ, which is a patient-reported outcome. The worse that is for patients, it actually led to worse health outcomes, and that means patients suffered a worse... They had more respiratory hospitalizations, they had a higher mortality rate, a higher risk of transplant. And I think if you just look pretty simply at what is cough doing to the patient, one of the patients on our trial coughed 1,500 x in a day.
I think on average, you can see about, you know, they can cough up to 700 x in an hour. So think about that trauma and the micro tears and inflammation associated right at, right at the lung. You know, there's, there's a reasonable hypothesis to test that over a period of time, that this could lead to worsening of the disease in, in some way, shape, or form.
And I guess, what endpoints or how could you, would you track this in clinical trials, or would it mostly be in the form of an extension study after a pivotal study or this phase II-B?
Yeah, I think-
Yeah, I would— Go ahead, Farrell. Yes, please.
I was gonna say, I mean, our phase II-B CORAL study, the dose-ranging study that Jennifer mentioned, is a six-week trial, and that's a relatively short time period to notice anything in terms of FVC or, or any health outcome changes. You know, that would really have to wait until the pivotal study, which, you know, we look to have around 52 weeks of controlled safety data. And you can look at FVC, you can look at oxygen saturation, you can look at these health outcome measures, which are important: respiratory hospitalizations, mortality, transplant risk.
Okay. So the CORAL trial, ongoing and started recruiting patients right now?
Yep.
Any timeline? May be too early, but any timelines in terms of when enrollment, on enrollment, and I think you have a sample size re-estimation analysis, kind of planned, scheduled for later this year?
Yes. So yeah, that study started right at the end of 2023. It is up and enrolling. We do have patients in the study. This is a big study. It's, you know, we've-- we're gonna be in 10 different countries, 60 sites. IPF is a competitive area for development, not COPD specifically, but IPF overall, so, you know, we're competing for patients. We are on track, so we're bringing up a lot of the sites still. I think those are scheduled to be fully on board by late Q2. And we've given guidance, sort of the milestones along the way. We look to complete enrollment in that study by the end of this year.
You're right that when 50% complete, we'll do a sample size re-estimation w e estimate that'll be the second half of this year, and we expect full top-line data in the first half of next year. So, we reconfirmed our guidance. We are still early in the study, though. We're on the-
Yeah
... first half of this study, so, you know, lot of road to cover between here and there.
Yep, and the SSRE analysis, you don't take a hit on statistical powering with such an exercise?
You don't. You probably remember, Serge, we did this in our PN trial. So essentially, the way you don't take an alpha hit, they're used a lot in phase II areas, where there's not a lot of data available for powering a study. And so it's a good way to not... You know, in the old days, you used to just over-enroll studies to make sure you didn't miss stat sig on something. Now, you're able to dial it in a lot better, and the way you don't take an alpha hit is essentially you pre-specify a conditional power range.
And you only get one of three answers back. Y ou either find out, yes, your powering's fine, you're on track, keep going o r, your drug's working, but you need to adjust your sample size, it has to be in that conditional power range you pre-specified, which we tied to essentially clinical meaningfulness. Or you're outside of your conditional power range, and you can sort of decide what to do with that. The answer you don't get, like on a full interim analysis, is if we're already at stat sig at that point, we won't know that. We'll just only get the notice that you should carry on. So, yeah, it's a great way to, I think, dial in your sample size once you get halfway through.
Okay. Are there any limits on how, you know, how much you can ramp up the sample size?
There is. That's a key upper limit that you have to set. We set it, for this trial, it's 400, which is linked to a 25% clinical meaningfulness change.
Mm.
But the nice thing is, it's not sort of our sample size now is 160. It's not 160 or 400. They literally come back with a number, sort of based on the first 50%. So, it can be anywhere in that range as you move up.
Got it. All right, so data potentially in first half next year, 2025.
Yep.
I know we're jumping ahead here, but any idea of, like, what a phase III program could look like? I'm sure you're still using the cough monitor, but I guess in terms of dosing and patient size.
Yeah. So we've been engaged in discussions with FDA around this already. I think we are planning on running two pivotal studies. They'd probably be a lot larger than what we're running in this study. I mean, we'll have to see the effect size, but, you know, sort of guessing it's somewhere around 50 per arm, maybe a few more, but not a big... We'll end up probably dropping one dose. We'd love to take forward a couple of doses into the next study. Again, this is all data dependent. Primary endpoint, we don't plan that that will change, and I think most of the secondary endpoints are also pretty fixed.
What we will have to do is find that anchor and sort of do all the work you do at the end of phase II to validate sort of, you know, your PROs as well. So we'll do that work, but I think we've also, there's a lot of precedents in the IPF world that the agency wants 12-month controlled safety. So we would have two studies. They'd be 12 months of safety. The efficacy read, really similar to if you look at the Bellus program in RCC, would probably come around three months or six months. So, you know, a year-long study, but efficacy read at three or six months, and then the subjects would continue through to get your long-term controlled safety.
Okay.
We have a pretty good idea what that looks like.
Yeah. And then some of the other studies you're running as, I guess, in concurrently with the phase II-B dosing is the human abuse liability study. I think that's expected to read out later this year.
Yeah.
Maybe just talk about why. Yeah, why the study and how it's designed?
Yeah, happy to do that. So there's this drug is broadly in the opioid class, but it is this mixed agonist-antagonist. It is known by the DEA. It is unscheduled. It's been around a while. There's actually been a lot of preclinical work done on the molecule, and sort of it's been around for a while, so this is not an unknown molecule. About 15 years ago, the FDA, when sort of the whole opioid thing blew up, started having companies do these human abuse liability studies. Not just opioids, by the way, CNS active drugs in general. So this is sort of the last piece of the puzzle we need to put in.
I think we feel comfortable w e actually didn't need to do this until we filed the NDA, but we decided to do it now just to get the data out and digest it for not only investors, but also strategics. The design essentially is three doses of our drug at single dose, low, sort of your marketed dose, and high dose, versus a comparator and versus placebo. All this has been sort of discussed with the agency, the doses of our drug, the doses of our comparator, and what the comparator is, which in this case is butorphanol. The reason butorphanol was selected is it looks mechanistically the most like our drug. We have a mu antagonist, kappa agonist. They have a weak mu agonist and a kappa agonist, so sort of the most similar.
It is a Schedule IV drug, which, you know, Schedule IV, a lot of people confuse that, you know, it's highly addictive, and it's Schedule II or nothing, and that's just not true. There's a lot of Schedule IV and V drugs that are things like tramadol, sleep aids, the benzos. That's the category butorphanol sits in. My own expectations, this drug's been around, it's been unscheduled. It's in an injectable form now, which is the most abusable form. Also, the two components of our drug, all mu antagonists, things like naloxone, naltrexone, are all unscheduled, and the only kappa agonist approved, Cara's drug, is unscheduled. So it doesn't seem very logical to me that each of the components are unscheduled, and the overall drug in an injectable form is unscheduled. Assuming the data is sort of consistent with that, I think we'll, we'll remain unscheduled.
Yeah. And has the injectable formulation been through a similar study?
So it went through all the studies that were required at the time, which were mostly all, they were all preclinical studies, but pretty rigorous. I mean, there's papers out on them. And then, the DEA continues to monitor for any kind of abuse activities, which there's not. This is a new, this is kind of a new standard over the last 15 years, and it's why it's the last box we've got to check.
Okay. And then, the other smaller study is the phase I-B. I think you've described it as a respiratory physiology study.
Yeah.
So that's gonna be... I think it's tracking a little later than the human abuse liability study, but maybe just highlight what, what the goal is behind that smaller study.
Yeah, no, it's a good question, and this is an interesting study, and we've guided towards getting an IND open around that the first half of this year. I feel pretty comfortable in that, and then we'll roll the study out for everyone. But essentially, we're answering some questions around- broadly, opioids have a respiratory depression black box warning. That's really more around the mu agonist. The mixed agonist-antagonists actually have been known to have a ceiling effect on re- they, you know, they don't see the same problem. And in all of our- we've had this in over 1,000 patients, we've never seen respiratory depression.
However, we are working in a pulmonary-impaired, you know, very sick group in IPF, and so we've carved out in the studies we've done to date, sort of a special group, which is what's called the sleep disordered breathing patients, so people on CPAP machines, for instance. The FDA was sort of circling around questions in that group, and so we decided at first, we were gonna try to monitor an outpatient setting, which is really difficult to do because the time you want to really look at these patients is when they go to sleep, and they're on their machines. So we decided to just bring them all in-house. We're doing a pretty sophisticated, you know, characterizing their respiratory physiology.
The goal is to, as we head into phase III, I would say there's two goals of the study: define the patient population, so determine if there's any group that should be excluded. And also, I think, sort of as my Co-Founder, Tom, does, he starts building in all these interesting scientific things. So he's also doing, while he's got them in-house for about eight days, they're doing a lot of looking at when you're coughing, what's happening to your lungs at that time, and sort of linking to what Farrell was talking about, about, you know, this is more than just a bothersome symptom. There's actually sort of issues going on at the lung level. So I think there's gonna be sort of a treasure trove of science that comes out of this study. But ultimately, we're trying to define the phase III patient population.
Okay, so this is mostly geared for IPF cough, not necessarily for refractory chronic cough or anything?
Right.
Okay.
It's all IPF. Well, the only people coming in the study are IPF patients.
Got it. Okay. All right, let's move to refractory chronic cough, where we'll see data, I think, later this year, from the proof of concept. But maybe before we talk about the, the actual trial, we can talk about the pathology and how it's different than IPF cough and why nalbuphine could have a role there, too.
Yeah, Farrell, you want to talk about sort of this and all the commercial stuff that I know Serge is gonna follow with here?
Sure. You know, when you look at, you talk about the pathology, sir, and the pathophysiology really behind nalbuphine in RCC, and it goes back to our central mechanism, and that's the differentiation. We work both centrally and peripherally. And so when you look at where all the signaling could come from, whether it's structural in the case of IPF or whether it's potentially a hypersensitivity disorder in refractory chronic cough, they all flow up to the central nervous system in the brainstem that modulates cough and breathing. And so that's why we think that, you know, the results we saw can now hopefully translate over to the refractory chronic cough population. I think when you look at what's different between these populations, we talked a lot about, well, could it actually impact the underlying disease of IPF? T hat there's potential there in IPF.
When you look at the refractory chronic cough, we're not gonna be impacting the underlying disease of asthma or gastroesophageal reflux disease, or upper airway cough, which is a fancy word for postnasal drip, right? So it's these are known conditions, and cough is just quite refractory. I think how you look at them similarly, though, is it has a similar impact on quality of life. I think the burden of cough on these patients is similar, and I think what you have is you just have a little bit younger of a population when you look at refractory chronic cough.
Yeah. Refractory chronic cough is, I think you mentioned it earlier, has been a difficult indication. A lot of failures, but maybe just highlight how that your mechanism is different than kind of the, the P2X3s that have also struggled a little bit here. And I think there's been some other drug classes, drug classes that have also, not, not met their, their efficacy endpoints.
So, I think there's really two factors at play here. One... or a couple, right? One is the mechanism, as you go back to, and we've talked, the central versus peripheral mechanism. We think a central mechanism is important in order to be successful in refractory chronic cough. I think when you look at some of the previous failures, unfortunately, from things like gefapixant, you learn two things. One is that they're, you know, they have efficacy, but there's a challenge in working across the broadest set of patients, right? And so what some of the strategies that have been employed by Bellus and GSK is this enrichment strategy, to look at the higher cough counts, and that only accounts for about roughly a quarter of the population in refractory chronic cough.
I think the second thing when you look at the refractory chronic cough is a high placebo rate. And I think, unfortunately, gefapixant got hurt by that, just being first in the category and really looking at this in a phase III design. And I think there are some interesting mechanisms that we can learn off of from the, the Bellus compound, the camlipixant compound, that we can take into future designs of our trial in order to help mitigate some of that placebo rate.
Yeah. In terms of the market opportunity for refractory chronic cough, obviously much bigger than IPF cough.
Yeah.
If you can just, you know, give us a few numbers, and maybe if you can highlight what they currently are treated with?
Yeah. So the market size, I'd say there's probably a lot of debate in the market size, right? The market for chronic cough as a whole affects up to 5%-10% of the population, right? So if you're just looking at raw numbers, you're looking at 12, 12 million, 13 million patients in the U.S.. But when you start to dwindle that down into the addressable patient population, which we estimate to be about 2 million-3 million, the reason being is those are the patients that are presenting to doctor's offices. Those are the patients that are uncontrolled on current medications. You start to get to that 2 million-3 million number, which we think are those with both the moderate as well as high cough frequency, that we would be able to hopefully address in the population.
How they, you know, kind of present what they're taking today, physicians are trying a whole host of other off-label therapies, right? They're trying Tessalon Perles. Very few are using other opioids, like low-dose morphine, in order to treat these patients. It's probably more common in Europe than it is in the United States. But they're trying things, right? And there's nothing that's really been able to work. There's even over-the-counter codeine cough syrup. But when you go back to the trials where these have been studied, and whether it's a PRO endpoint or it's an objective cough monitor, they've unfortunately not been, you know, positive. I think that what you do see as positive are the ones that are centrally active.
Yeah
... and I think they haven't shown the depth of response that we were able to prove in IPF.
Okay. So the RIVER proof-of-concept trial, I guess similar a little bit to the CANAL trial in the sense that it's a crossover, just exploring one dose. But maybe, maybe if you can talk a little bit more about what kind of patients is it enrolling and where you are in terms of enrollment.
Yep. We are doing the dose range again, Serge. We've dropped the highest dose, but we'll start at the 27 mg, go to 54 mg, 108 mg. It's a three-week study. We're washing subjects out for three weeks, and then they cross over and go to the other side. I think to Farrell's point, we've got a sample size of 60 people. We are stratifying it, so we've got 30 people in the 10-19 coughs per hour and 30 people in the greater than 20 coughs per hour. We really want to leave this study understanding, with our central mechanism, you know, are we able to reach this much broader patient population besides just the sort of less than a third Farrell alluded to? We initiated this study in the fourth quarter of last year.
It's moving along nicely. W e had guided towards data in the second half of this year. We're still comfortable with that guidance. Yeah, just really excited to get to data here. I think, it's been an area that's had a lot of failures, but a lot of interest, and a lot of interest by big companies. So we feel that, you know, there's a been sort of this common wisdom that IPF's a higher bar than RCC is in cough. It's why a lot of people have moved away and we had such strong data in IPF. So we're excited for maybe an option, this option for patients.
Does what Bellus has done kind of give you a roadmap on what you want to achieve to show proof of concept in this space?
Yeah, definitely. I mean, I think both Merck and Bellus, we're sort of the beneficiaries of two people over the wall. Unfortunately for Merck, they're probably not gonna make it. But I think there's been a lot of learnings about sort of what can go wrong in these trials, and I think sort of getting the subjective cough monitor out there and validate a lot of secondary endpoints. Definitely, I think we're in a really sort of fast follower mode, where we can learn from what others did and be able to keep moving.
I think Bellus also did a really nice job, that, as Farrell mentioned, the placebo effect here has been challenging, and I think Bellus added some nice innovation into their phase III trials around adjudicating the diagnosis, making sure you're really getting the right patients, and then also doing the placebo run-in. You know, those are lessons we can pick up and learn, and we did just hire the head of clinical development from Bellus. GSK-
Yeah
... didn't keep any of those employees, so we've been raiding around those people and picking up the ones that make sense for us, so we're excited about that.
You talked a little bit in terms of the baseline patient population of the different cough counts. Maybe you can just break down what level of cough counts you'll be targeting, and how that's part of the enrichment of the patient population.
Yeah, so you know, Bellus, when they moved on, and Merck too, they both put out data that really showed their drug didn't work in those 10-19 coughs per hour. It only worked in this enriched group. In our IPF cough data, we did an analysis that showed the drug worked consistently, whether across all baseline cough counts, which, if you remember in that study, we had people as low as 3 per hour, all the way up to 92 per hour. So, you know, and then you multiply that by 12 or 24 to get to the total coughs per day. So we had good confidence, at least in IPF, that baseline cough count wasn't impacting who responded and who didn't.
You know, we're just really excited to be able to sort of look at these two groups of sort of more moderate coughers and the severe coughers, and get a good sense of how we move forward.
Okay. We'll see this data in the second half of this year?
Yeah.
Sounds based on the IPF cough data, you're pretty confident in seeing a signal?
I mean, you know, as confident as you ever can be in a phase II-A. But fortunately, we've got some sort of precursor here, and I think, as Farrell sort of elucidated, based on the mechanism here, it makes a lot of sense. I would also say the, the only drug that's really ever been shown to work in RCC and is used clinically is morphine, which I think the... But they have to keep the doses so low because of respiratory depression, and then they do have all sort of the Schedule II issues, but it is the only validated mechanism, and I think it's back to sort of working at that brain stem. So not only I think our data from IPF, but there's good morphine data in refractory chronic cough. So it's sort of those two links that I think makes this a good experiment to run.
Yeah. And how would you say the environment in refractory chronic cough has changed just post the Merck ad com and this... I think they did get a second CRL. Has it scared people from attempting the indication, or they've kind of just modified their programs to be in a better spot to get a signal?
So interestingly, and Farrell, correct me if I'm wrong, there's not a lot of players left in refractory chronic cough. They've all sort of failed and gone away. And, you know, there's the GSK program, and I think that's encouraging because GSK obviously paid $2 billion for Bellus, and I think they've guided that they think this drug can be what, Farrell, $2 billion-$3 billion opportunity for them? Something like that.
Yeah.
So it's exciting in that way. I think your point's right, though. I do think, you know, particularly investors start wondering, when everything's failing, what's going on here? Is this just gonna be too difficult of a condition? And I, I would say the KOLs are also kind of worried about that whole perception, that this is a challenging area, and people will start getting scared. So I, I find we get a lot of support. I think people are starting to migrate towards maybe these centrally acting compounds are the answer here, and there was so much work put into these peripherally acting mechanisms, all of which really have failed except for Bellus's. So, yeah, I think it's a good time to be doing this, but, but I agree with you. I think at some point we've gotta have something work here.
Yeah. But we'll get an answer shortly, so-
Yeah
... maybe we can just talk about the IP, just an overview of the IP around nalbuphine and the different indications.
Yeah, it's a great question. It's an old compound, so no composition of matter. There's sort of three layers of patents. The first is the extended release formulation patents, which start to roll off in 2029, so won't be around all that long. Really, the core of the protection is around method-of-use patents, and we were able to get issued quite broad patents with all the claims intact that we filed for because there'd been no work done here, so this was all novel and not obvious. That patent's been issued. It goes out to 2039. We also have some specific patents around certain patient groups, the elderly, you know, hepatic-impaired, renal-impaired, and so those are all things in the label that you build your little fence around.
Those go out longer, but I think of the core of this protection as that 2039 patent.
Okay. And then maybe we can get Lisa involved here, and just give us an overview of the financials before we wrap up.
Sure. Like Jennifer mentioned at the beginning, we're a well-capitalized little company. We ended December with $83 million on the balance sheet, in cash and investments, no debt. We guide cash runway into 2026, so, you know, we get through inflection points on all the trials that Jennifer spoke about today, and then we have a nice, about 12 months of runway after that.
Okay. I guess just to finish off, is there anything at this point, with the data we've seen, that is still kind of underappreciated or misunderstood, about nalbuphine?
I mean, I would... I think the two things I would have people take away is not all opioids are the same. People hear opioids and get scared, and the whole reason I started this company is I felt this compound was part of that solution. I never would've waded back into that whole mess. So, you know, we've talked about the mechanism here, and we're running the study to sort of put our money where our mouth is. But I just think people need to understand that this whole class of drugs, these mixed agonist-antagonists, could be a really good answer, I think, for a lot of sort of what's going on in the opioid space.
And then the second thing, Serge, you did a nice job of interrogating, but just the sort of translatability of that IPF cough data, I think, broadly across cough, and I do think the common denominator is that central mechanism. So we're excited about that. I think if we're able to prove that here, it really sort of turns that cough world a little bit upside down and probably changes sort of how people start viewing the development compounds going forward. So those are the two things this year I think we're really excited about getting data around.
Okay. Well, I think we'll wrap it up here. Thank you for the overview. Obviously, some key data over the next 12 months, starting with the second half of this year, I think really can be transformational for the company. So-
Great
... thanks very much.
Thank you for having us, Serge.