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

Good afternoon, and welcome to the Trevi Therapeutics webcast presenting the top line results from the human abuse potential, or HAP, study. [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 the 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 quarterly report on Form 10-Q. 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 webcast over to Jennifer Good, Trevi's President and CEO. Please go ahead.

Good afternoon, and thank you for joining us for the top line data presentation of our human abuse potential study. We are excited to share the positive results from this study; and following the presentation, we will open it up for Q&A. Joining me today on this call are my Trevi colleagues, Dr. Thomas Sciascia, Trevi's Co-Founder and Chief Scientific Officer; and Dr. Jim Cassella, Trevi's Chief Development Officer. We are also joined by Dr. Jack Henningfield, the Vice President of Research, Health Policy and Abuse Liability at Pinney Associates. Jack has a deep history with human abuse potential, or HAP, studies. I think he has touched every HAP study conducted over the past few decades. Thank you, Jack, for joining us. I know the analysts will appreciate your expert perspective. Before Jim goes into the results in more depth, I wanted to anchor the discussion in a few facts surrounding both nalbuphine, specifically in human abuse potential studies generally. First, nalbuphine is not a new molecule to the FDA or DEA. It has been approved as an injectable pain drug and has been reviewed and unscheduled for close to 40 years. Nalbuphine is part of a class of drugs called mixed agonist-antagonist. This class of drugs were developed in the '70s to address the growing drug abuse problem. Nalbuphine specifically is a kappa agonist and mu antagonist or KAMA. This is important for several reasons. First, the DEA noted in its review of nalbuphine that its potent new antagonistic effect can precipitate drug withdrawal in opioid-tolerant patients, so it is not likely that drug addicts would seek out nalbuphine if they're taking other opioids. Second, the 2 components of nalbuphine's mechanism are both unscheduled. Mu antagonists such as naloxone and naltrexone are unscheduled, and the approved kappa agonist, KORSUVA, is also unscheduled. Finally, nalbuphine has a long history of real-world evidence of a lack of abuse as monitored through the very comprehensive drug surveillance that is done by the DEA. So this drug is not being looked at the FDA and DEA for the first time, and the question will be whether we generate any data that changes their viewpoint on the likelihood of abuse of nalbuphine when it hasn't been seen in real-world evidence over decades. Slide 6 is a reminder of the scheduling classifications used by the DEA. It is important to note that not all opioids are the same. You see a range on this slide from Schedule II, things like oxycodone or fentanyl, to unscheduled opioids like nalbuphine or difelikefalin, depending on the actual mechanism of the drug. You will also note on the right side of this slide that the DEA continues to review this list regularly and in 2023, concluded that nalbuphine should remain unscheduled. I also want to briefly review the FDA guidance on HAP studies as well as our interactions with the FDA. HAP studies are required for central nervous system or CNS active drugs, and there was new FDA guidance provided in 2017 on how to run these studies. So although nalbuphine is already unscheduled, we are required to conduct this study to bring the package up to current day standards. These standards require the assessment of 3 doses of your active drug, both therapeutic and supratherapeutic doses. Our HAP study compares oral immediate-release nalbuphine against an active comparator or IV butorphanol, which is a Schedule IV drug as well as against placebo. As we have worked our way through this study, we have been in active dialogue with the FDA to get their concurrence on the active comparator, the dose of the active comparator and our proposed doses for nalbuphine. We had also submitted the full protocol and stats plan to the FDA prior to conducting the study. I will now turn it over to Jim to go over the study design and results.

Thank you, Jennifer. I'm happy to share these results with you today that support the low relative abuse potential of nalbuphine compared to scheduled drugs. Let me review the study design and objectives with you, and then I will go into more detail on the end points. This was a randomized, double dummy, active and placebo-controlled 5-way crossover study. Subjects were recreational opioid users and first entered a qualification phase where they had to pass 2 tests before moving forward into the treatment phase, which is the main part of the study. First, they had a naloxone challenge to ensure that they were not currently abusing opioids. Then they were given IV butorphanol to ensure a minimum drug-liking response that could be discriminated from placebo. If they met minimum response criteria, the subject was considered eligible to enter the treatment phase. Subjects were then randomized into 5 double-blind, double-dummy treatment arms and were given an IV and oral solution at each dosing day. There was a minimum 4-day washout period between each of the 5 arms. The primary objective of the treatment phase was to understand the relative abuse potential of nalbuphine against both the active comparator of IV butorphanol and placebo. The primary end point was a bipolar drug-liking visual analog scale, or VAS, where 0 represented strong disliking, 50 means neither like nor dislike, and 100 indicates strong liking. The primary end point analysis was based on the peak drug liking VAS or VAS Emax for each of the treatment arms. The first analysis to discuss is validity of the study design. By that, I mean whether the study design was appropriate to pick up a drug-liking effect of the active comparator, IV butorphanol. This is a common requirement for these studies and shows that the study design is sensitive to detecting a minimal drug-liking response. In this case, and consistent with other HAP trials, the butorphanol response had to be at least 15 points higher or more liked on the VAS scale compared to placebo. The results demonstrated a statistically significant higher likability for butorphanol compared to placebo with over a 30-point difference and thus, validates the study design. Next is the primary end point analysis in regard to drug liking of 3 doses of nalbuphine as compared to butorphanol. We are very pleased with -- that both doses of nalbuphine that were used in our clinical program, that is the 81-milligram and the 162-milligram doses, demonstrated a statistically significant lower drug-liking response compared to butorphanol. For the FDA guidance, we studied a supratherapeutic dose of 486 milligrams nalbuphine and found that the drug liking was numerically lower than butorphanol but was not statistically significant. To put these nalbuphine doses in perspective, remember that we have studied a dose range of 27 milligrams to 160 milligrams in our chronic cough clinical studies. Consequently, in this study, we tested a dose that was 3x the highest clinical dose tested in our clinical program. In summary, with regard to the primary end point, we see less drug liking with nalbuphine compared to butorphanol. These results suggest that nalbuphine has lower relative abuse potential than a Schedule IV reference drug. We included a number of secondary end points in the study, in which the subject responded to questions or statements that are typical for HAP studies. One question asked on a bipolar VAS scale was, "At this moment, I would take this drug again." This is a relatively ambiguous question in which the subject might consider a number of positive or negative aspects of the drug. In our data, we see a similar response for all doses of nalbuphine and butorphanol and importantly, do not see an increasing willingness to take the drug again as the dose of nalbuphine increases. In fact, we see a trend that subjects would be less likely to take the drug again as the dose increases, which is an important consideration for potential abuse. A more direct and clarifying secondary end point is represented by the VAS response to this statement, "At this moment, I feel high." Note that this end point is assessed on a unipolar VAS ranging from 0 to 100, where 0 is not at all and 100 is extremely. The data show a lower likelihood of feeling high across all doses of nalbuphine compared to butorphanol with the 81-milligram and 162-milligram doses rated at about half the feeling high ratings of butorphanol. These data are consistent with the primary end point findings. There is a similar story with another secondary end point using unipolar VAS in which the subjects respond to this statement, "At this moment, I feel good drug effects." Once again, there were lower scores for nalbuphine across all doses, with the 81-milligram and 162-milligram doses of nalbuphine rated approximately 30 units less than butorphanol. The totality of the results from this HAP study are encouraging, supporting a low relative abuse potential with nalbuphine and will help build the case as to why nalbuphine should remain unscheduled as a commercial product. I will now turn it back over to Jennifer for additional remarks.

Thank you, Jim. We are happy to have completed a valid and robust study, and we believe the results reaffirm what was already known about nalbuphine and its low relative potential for abuse. Although we have focused on the HAP results on this call, I want to remind everyone that these results are only 1 piece of an overall 8-factor plan that is submitted at the time of the NDA to inform scheduling considerations. The DEA will make the final scheduling decision, with input from FDA and HHS after NDA approval. To date, we believe the available data across all of the 8 factors support keeping nalbuphine unscheduled. Public health risk is a critical aspect of the 8-factor plan. Scheduling is used as a tool by the FDA/DEA to prevent public health risks and shift prescribing habits from higher-risk substances to lower-risk substances. As you all know, we are studying nalbuphine ER as a potential therapy in severe chronic cough conditions. Because there is nothing approved in the U.S. for either of the conditions we are studying, physicians have to resort to writing off-label scripts for therapies that have limited efficacy. In the U.S., from a claims database of chronic cough patients, 71% are taking opioid-containing cough suppressants. A majority of these are mu agonists, which are potentially dangerous for patients for a number of reasons, including a higher potential for addiction, other safety issues as well as the lack of efficacy, so there is a public health incentive to shift these patients with severe cough from drugs with known safety and addiction issues to a more efficacious treatment with lower relative abuse potential. Separately, from our own research, chronic cough physicians have indicated that there would be little to no impact on how they would prescribe Haduvio if it were to be classified as Schedule IV or V. That is important context for how we think about risk in scheduling as it relates to the indications we have chosen to develop. We have several important clinical development milestones coming up in the next few months in both IPF chronic cough and refractory chronic cough. This HAP trial is the first of many data readouts from Trevi in the upcoming months. We will report the results from the sample size reestimation or SSRE in our Phase IIb CORAL IPF chronic cough trial in the next 2 weeks. We expect to have the top line results from our Phase IIa RIVER RCC trial in the first quarter of 2025, followed by the full trial results from our IPF CORAL trial in the first half of 2025, assuming no increase to the sample size. This is an exciting time for Trevi and the patients we look to serve. We also have a strong balance sheet with sufficient cash to get us through these clinical milestones and more than 12 months of runway in the second half of 2026. We will now open it up to Q&A, and as the operator queues up the Q&A, Jack, do you want to make a few overarching comments?

Sure. Thank you, Jennifer. I'm Jack Henningfield, and I'm pleased to be advising Trevi on this new potential treatment for chronic headache-related disorders. I've been advising on abuse potential-related issues, including the HAP study interpretation. This doesn't come new to me. I've been involved in abuse potential assessment research, including HAP studies, for more than 45 years and drug scheduling. And that included working with DEA and FDA beginning in 1980 as part of my official duties as head of the abuse potential and clinical pharmacology programs at the National Institute on Drug Abuse. By the way, from a scheduling perspective, a major consideration for oral nalbuphine is that it is not a new chemical entity. As Jennifer mentioned, it's been available and marketed for more than 40 years and without scheduling since 1977. Thus, there's nearly 3 decades of experience of -- or more than 4 decades of experience with nalbuphine as an unscheduled medicine with little evidence of diversion, abuse or contribution to overdose deaths. So the big question to me was did the HAP study provide evidence that would support scheduling nalbuphine because scheduling is generally for the substance, not just a new product. That would be a big thing for FDA to recommend. It would be unusual.

Thank you, Jack. That's helpful. I'm sure you'll get a lot of questions. So operator, I'll let you go ahead and have the first question.

[Operator Instructions] Today's first question comes from Faisal Khurshid with Leerink.

First question I had was just how should investors think about the dose response that was seen here. Was this a surprise to you? And more importantly, how does the FDA think about -- or the DEA and the CSS think about that supratherapeutic dose level?

Yes. So Jim, why don't you answer the dose response, and we'll let Jack comment on how FDA or DEA might view it.

Sure. That sounds great. So it's a good question. I think we need to look at the data in its totality, and really, you'll see there that while there appears to be clearly higher responses at the supratherapeutic dose, it's a relatively flat dose relationship as we double the dose between the 81 and the 162. There's really not much of an increase there. And then we get to the supratherapeutic dose, where there seems to be a greater increase. And we also have the example of the take the drug again case, where we actually see more of an inverted dose relationship where the lower dose actually performs a little bit higher than the highest dose. So I think the concept of a dose response relationship here is somewhat unclear. It looks to be rather an inconsistent relationship here, with a flat part of the -- 2 of the doses responding fairly similarly with the supratherapeutic dose giving us a greater likelihood of a response on any of the questions. So I think it's not very clear that we have a true dose response relationship in the sense that you would think of one. So I think that, Jack, maybe you have some other perspective on this.

Sure, Jim. Thanks. I think you hit the main points, including the inconsistency and the question, I would -- would I take this drug again. Even though that's officially a secondary end point, that's a very important question. And there, the dose response curve for what it is, is in stark contrast to what we see with classic drugs of abuse. With classic drugs of abuse, and I've studied dozens of them, you see a sharp dose response curve with increasing scores generally across most, if not, all of the measures related to abuse including I would take the drug again. So when me and my colleagues looked at this, we thought, well, this does not look at all like a classic drug of abuse despite the bump on liking at the whopping triple, well, depending on how you look at it, triple the highest therapeutic dose or several times the lowest therapeutic dose.

And I would just add, Jim, all doses are below butorphanol numerically, which I think was always sort of our bogey that we were trying to hit. So even at the very highest dose, it's still below.

I think that's the one consistent finding that we have in the study.

Yes, exactly.

Got it. That's helpful. And then just a follow-up that I had here was in terms of potential scheduling decision, does the kind of commercial dynamics that you expect, if you have a potential scheduling designation, is it different in IPF cough compared to chronic cough at all?

Jack, I'm going to let you give your expert opinion, but I will say, Faisal, as you know, the molecule is going to be scheduled. They're not going to schedule by indication. I think maybe some of the public health considerations could be different, you could argue, but I'm not so sure about that. I think, Jack, I'll let you sort of comment on how you view the public health risk here.

You're spot on, Jennifer. The first, what we call, bifurcated or trifurcated scheduling is extremely rare. The so-called Vicodin category of low-dose hydrocodone and acetaminophen was moved to its parent's schedule in 2014. It's -- so scheduling is generally by law and in practice based on the substance, not the form and not the indication. That's the reason that the FDA is generally reluctant to put them in different categories.

Yes. I guess my question is more from a commercial perspective. For the Trevi management team, like do you think a potential drug scheduling designation matters more from the commercial opportunity in IPF cough compared to chronic cough?

Okay. I understand. Thanks, Faisal. So we've done our market research on this. Farrell has surveyed several physicians. We found that Schedule IV, V in IPF is completely irrelevant. There's no change in patterns. As you heard from my data, they're already using morphine and all kinds of Schedule II substances to treat these patients. In refractory chronic cough, there was a small effect in kind of the primary care population, but it's such a big population overall that we don't think it affects our opportunity, especially since we plan to go after more of the refractory patients that nothing else works for.

And our next question today comes from Leland Gershell with Oppenheimer.

Yes, question for Dr. Henningfield. Just given your vast experience with these types of studies and with scheduling decisions and so forth, I'm just wondering if you could put in perspective these results as compared to any maybe cases that you personally been involved with in the past, where HAP studies have been done for substances that may not be scheduled that could be considered for scheduling, and if you could align these results to results in the past from those cases and what the outcomes were?

Yes, there's a number of different kinds of precedents over the many years, but I'll give you an old one. Nicotine gum and patch were approved without scheduling, and nasal nicotine came along, and my abuse potential study showed a solid bump and increase in liking and all of the other measures. And so FDA was -- some of the people said FDA should recommend scheduling, and in the end, FDA did what it usually does, which is it kept it all on the same schedule. So it's rare that there are differences. In terms of adding something to the controlled substances out that has been available for decades unscheduled, usually, what drives that is a public health outbreak. And in fact, the comparator drug in this study, butorphanol, was not scheduled until 1997. And what led to it's being placed in The Controlled Substances Act in Schedule IV was an outbreak of diversion, abuse, overdose and other problems. We've never seen that with nalbuphine. So it doesn't mean that FDA out of a so-called abundance of caution couldn't recommend something, but it would be hard pressed to, I think, justify higher than Schedule V or more restrictive than Schedule V, and even that would require some justification because that would mean all nalbuphine would be placed under Controlled Substances Act. And again, that would be unusual to say the least.

And our next question today comes from Annabel Samimy with Stifel.

Thanks for sharing the data, and good to see confirmation of what we already knew about nalbuphine. So I just want to clarify, when the FDA reads these data, do they compare likability to placebo? Or do they look at it primarily against the comparator, butorphanol? Because I'm wondering if that might be confusing to some people.

Yes, it's a good question. I'll summarize it, but, Jack or Jim, jump in. The comparison to placebo is whether you can claim that you're similar to placebo, and there's a defined range that you have to be within 11 points of placebo. We're clearly outside of that, so we're not going to be able to claim we are placebo. So they're going to look at the comparator drug here. I would just cross compare, Annabel, a company you know well. Cara Therapeutics had the same fact pattern where, essentially, they were outside of the 11-point range against placebo. So they were more sort of likable than placebo but were statistically significant lower than their comparator drug, which was pentazocine. That's a pure kappa agonist, and that drug ended up unscheduled. So I think that's a good fact pattern for where we sit.

Okay. Great. That's helpful. And then you mentioned in the past -- or actually, you just mentioned on this call that the HAP study is only 1 aspect of the 8-factor plan. Can you just remind us what the other components are and whether this HAP was the biggest hurdle that you had to overcome to get through this plan?

Jack, you're the expert on 8-factor plan, so I'll let them hear it from you.

Sure. And one of the most important aspects of the 8 factors is the public health -- are the public health factors and those are factors 4, 5 and 6. And public health goes both ways. And the first way is, is there a public health threat related to the substance that requires -- essentially requires or warrants scheduling. And we've never seen that from nalbuphine. So that's factors 4, 5 and 6. Nalbuphine is about as clean as it gets on that scope. Conversely, there is a potential public health benefit, which if we were working on the 8 factor, we would work in, and that is the benefits of shifting people away from Schedule II opioids with chronic cough. And that's what a lot of them are getting right now. So those are the important things. Nalbuphine is low on respiratory depressant effects because it's a partial agonist. It has low physical dependence potential. It's low on basically all of the nonclinical measures. So it's -- all of this comes into play. The HAP study is one factor -- or one study in one factor. It's -- for new chemical entities, if there are robust findings and more robust than we see here suggesting abuse potential than in the past FDA was more likely or something that was a new entity with no experience in the real world, to recommend scheduling, and as many of you know, that's -- the DORAs, the dual orexin antagonists, were scheduled on the basis of a HAP. And a few years later, just the last couple of years, FDA has basically said in 2 different meetings that they were overly restrictively scheduled, and maybe shouldn't have been scheduled. So FDA, I think, has been much more cautious about jumping to conclusions when you've got very low abuse potential substances. By the way, the term FDA often uses is if they're meaningful abuse potential, meaningful enough to warrant scheduling.

And our next question comes from Deb Chatterjee with Jones.

Do you hear me?

Yes, we can hear you.

Okay. Great. So could you maybe clarify one thing for me? So you mentioned that there should be like an 11-point difference to be a meaningful more likability between the 2 groups. Is it the same for the primary as well as all the secondary end points?

No. Thanks for the question, Debanjana. So the 11-point reference is only to placebo in the stats. It's not relevant to the butorphanol comparison or all the other secondaries, only to the placebo, and it's not relevant to the secondary end points. It was really just that comparison.

I see is there a threshold based on which FDA or the DEA might consider what is more likable compared to butorphanol even if that's not statistically significant?

Well, so the 2 doses were statistically separated from butorphanol. So our clinical doses are statistically separated from butorphanol. So that's clear. I think the supratherapeutic dose, which is more than, well, dose, for sure -- by the way, in an oral immediate-release solution, recall, we have an oral extended release, which is going to blunt the Cmax. That's what I think Jack's kind of referred to. This is going to be a Gestalt analysis. You can't point to one thing and say it's X amount and you're in the clear because they're going to look at all the secondaries. They're going to look at the history of this drug. They're going to look at our clinical database, and they take a bigger view than just what's the separation here. So the answer is no. We run the study. They look at the totality of the data, and they look at that in the overall look at the 8-factor plan.

And our next question today comes from Serge Belanger with Needham & Company.

I guess first question. Jennifer, in the past, you've talked about the next steps would involve submitting this data to FDA. But curious when do you expect to hear of, I guess, an indication from the agency on whether they'll maintain a status quo or contemplate schedule changes? Would that be when you submit an NDA? Or would that be part of discussions end of Phase II meeting? And then...

Yes. Go ahead, Serge. Finish your question.

I'll let you answer. The next one is for Dr. Henningfield.

Okay. Good, because I'm getting old. I forget questions if you stack them up too much. Yes, we -- there won't be a final determination until the NDA's submitted, approved and then they'll sort of rule on it at the time, just like what happened with Cara. Cara sort of got it as part of their approval. I will say, though, and Jim, feel free to jump in here, we have been keeping the FDA informed. We will send them these results. We will definitely have a conversation probably with the CSS consult in our end of Phase II meetings. These are important conversations to start helping the division understand that this opioid doesn't look like all the other opioids. So we'll definitely be having those conversations, and I would say our SVP of Regulatory has already done a very good job of having those doors open and keeping them informed. I'll turn it back to you to ask Jack your question.

Yes. So in terms of some of these older chemical entities that have undergone increased scrutiny by the FDA and DEA, have any of them undergone any scheduling changes over the last few years?

Say that again? Was there...

In terms of some of these older chemical entities that have been out in the market for decades and are now under increased scrutiny by FDA and DEA, just curious if there's been any examples of some of them undergoing changes -- scheduling changes.

Yes. And there's actually not many but tramadol in 2014, and that was one where it was a very dicey call. And the FDA and DEA disagreed, quite frankly. And FDA made the argument that the world really needs a nonscheduled pain reliever despite some abuse and diversion and overdose. And some people have argued that scheduling tramadol, which is -- was pretty much pressured by DEA, it's hard to -- there's no simple answer to the opioid overdose problem, but there were a lot of people that were getting adequate pain relief with tramadol that didn't turn to much more deadly opioids. So that's one. I already mentioned butorphanol, and butorphanol was scheduled basically on the basis of public health outbreak of diversion, abuse and overdose, all things that we have not seen with nalbuphine over 4 decades. By the way, Cara's drug was mentioned. I can disclose because I copublished their findings with Cara, but that was approved on my birthday without a scheduling recommendation. And that was not a perfectly clean drug. But the FDA official, I think, wording was without meaningful abuse potential, and that's where, I think, a lot of us place nalbuphine.

And our next question comes from Mayank Mamtani with B. Riley Securities.

Yes. Appreciate the level of transparency here. So maybe for Dr. Henningfield, just a follow-up on the secondary end point, take the drug again. For butorphanol versus placebo separation here, it seems small. How should we think about the clinical relevance of this end point given, say, it's less than a 15 point delta? And it looks a bit lower than what we saw in the Cara study that you referenced comparing placebo and pentazocine. Just wanted to understand the clinical relevance of the secondary end point. And then I have a follow-up.

Sure. The -- with drugs that are relatively low abuse potential and comparators that are relatively low abuse potential, you quite -- to use a technical term, you get noise. So you're recruiting subjects for the studies that really like the low-abuse potential comparator. And I was discussing this with the director of the CRO that led this study, and we've had a lot of discussions. Basically, you see a lot of noise where it seems like almost anything that produces some kind of signal to the brain, they'll respond with some kind of liking. And if it's robust and consistent across all of the measures, that's one thing. But here, we're finding what we often see with such substances, which is what looks like noisy data. And I think that's part of the reason that FDA doesn't consider nearly as heavily the separation from placebo as the separation from the comparator and the shape of the dose response curve across all of the measures. Essentially, these studies are biased to be oversensitive, and I think from a public health perspective, if you're going to bias the study, that's what you want, but it means that you're getting a lot of people -- you're literally only testing people that say they really like butorphanol. And that's -- I'll use another technical term. That's a little bit of a weird population.

Another technical term and in which population. We do it all the time in drug development, Jack.

That's helpful. And I guess just for the company, maybe for Jen and maybe, Jim, as you look at this data, and obviously, you have a different -- very different population enrolled in CORAL and RIVER studies. I was just curious what safety information -- I understand the next update is really just a sample size reassessment but just obviously thinking beyond to RIVER full update you'll have, what sort of things we should be looking for. And lastly, how do these results inform at all your total sample size exposure requirements as you obviously think about Phase III planning, and obviously the studies you need to do for NDA planning?

There was a lot of stuff in there, Mayank, so I'm going to give it my best shot. But come back if we miss something. So I would say, overall, we were all very happy with these results. I think Annabel summed it well, which is sort of nothing to see here, which is what we always thought, but you never take studies for granted. I think it has no impact on how we're developing nalbuphine. We picked indications that are severe that I think we believe need some kind of therapy like this. So that's helpful. I think it shows you, Jack, sort of alluded to this, just some of the pharmacologic response. This is a potent compound that works in the CNS. So you're seeing some of that in the noise, if you will, so I think it just validates. But to some extent, we already knew that, right? We've had positive studies. So the drug works. You asked about safety. I wasn't sure if you meant this study, but my co-founder, Tom Sciascia is here, who oversaw that study. Tom, I don't know if you want to make a quick comment on the safety in the study.

So I think that across all our studies, the adverse event profile of the drug has been very consistent across all the subject populations that we've studied. And they're pretty much what one would expect with the CNS active drug, but there's really nothing that would make us alarmed that we have any signal that would think that the drug is being abused or that we have an abuse potential issue with the drug in terms of what we're seeing in safety surveillance across our populations.

Did we get that, Mayank?

Yes. I guess the thought around anything specific we should be looking for in CORAL and RIVER updates from a safety standpoint, I guess you answered it that no real change in how you're thinking about developing, just to clarify.

So yes, sorry, nothing here. I mean this is actually validating. I think that we're -- I feel very positive about these drugs that validate sort of the thesis. Think we bring a public health, as Jack keeps hitting on. I mean we're going to give people a much safer alternative that hopefully works better. I think just to set expectations on our SSRE, which is coming next, we won't have any safety data from that. We're just literally getting information around the sample size. And then when we report top line results, we'll obviously report out the overall results. I have mentioned before publicly our IPF trial. Our lead trial is running well, I would say, just overall the quality and sort of discontinuations and things like that have been low. So we're excited about that, and we look forward to seeing our SSRE results next.

And our next question today comes from Brandon Folkes of Rodman & Renshaw.

Maybe just first up to the expert. We talked a lot about the real world evidence on nalbuphine. Does the fact a lot of this real-world evidence has potentially been generated as an injection in a controlled setting in Haduvio will be an oral in the community, does that play into the scheduling decision or sort of complicate the potential to review the molecule scheduling?

Is -- does the...

Jack, I want you to take that. Yes.

I'm sorry, what's the last part of it?

He's asking if the fact that the real-world evidence is pretty benign, there's not any signs, but he's saying it's been an injectable all these years. Does that play into sort of their thinking here that we have an oral?

Yes. It plays in 2 different ways. The injectable is generally for just about any drug -- for most drugs, the injectable form is considered the most abusable form. And that's why for animal studies, it's injection studies across the board. So it would be unusual for something that is given orally to have a higher abuse potential. So that's reassuring. On the other hand, it's been more restricted. Access has been more restricted. But having said that, over 4 decades of experience, diversion from hospitals of drugs that are considered good drugs to get high on and good drugs to get liking, et cetera, they're diverted. And the United States is -- seems to be the canary in the mine shaft trying to find out creative ways to abuse just about anything that's out there that has -- that seems to be a good way to get high and euphoric. And this, over 4 decades, has not emerged in that category. So I think the FDA, out of an abundance of caution, as I often heard from them, said, well, you're going to make the [ temp ] bigger with an oral form, and we want to look at that oral form. We want to -- you to look at it with the HAP study.

And maybe just one for Jennifer and the Trevi team. You provided us some good data there on the prescribers regarding the scheduling. Have you done any work with insurers regarding Haduvio and how that may be treated differently if it is scheduled versus not scheduled?

No, thanks for the question, Brandon. We have not. We're waiting for sort of this next turn of data, our IIb and IPF and also our RCC data. And we'll continue to dig in. Farrell, my commercial guy is waving me down. Farrell, just chime in here.

Yes. I mean we've talked to prescribers in this area, and we've done prescriber research across the IPF and RCC populations. They don't see scheduling as a tool in order to manage the category, right? It's benign to them. It's really prescribers. And in both of those categories, we don't see an impact.

Yes. That's a good point. I listened to the payer call. There's so little options for IPF patients other than antifibrotics to actually treat the symptoms they're dealing with. I mean the payers basically said you can charge what you want here. It's a small category. We're not going to manage it. So RCC will be a different conversation obviously, but yes, a lot of room to move in IPF.

Our next question comes from Ryan Deschner, Raymond James.

Was pupil dilation measured? And if so, was that response in line with the primary end point in terms of the dose dependence of nalbuphine? And then I have a follow-up.

It was measured. I can't recall all the data off hand right now, but I don't think there was anything remarkable in there. There clearly was a response. It is an opiate. It does show a pupil response. I don't think there was anything unusual about the data, but I'm not sure if you could add anything to that.

I don't know have anything about that.

No, I don't have anything that -- to comment on at the moment. We basically focused on the top line data that really is connected to what we believe is important to the communication to the external world. We've got -- we've just gotten this data. We've got to really go and mine it carefully as we get ready for publications and academic disclosures and journals. So I can't give you the specifics and the details because we're really focused on what we thought was important to the investors.

Got it. And a quick one for Dr. Henningfield. In your view, what specifically did the take drug again metric evaluate in these patients in this study, differentiated from overall drug liking? And what is your interpretation of the inverted response?

The noise that you're getting makes it -- again, this is a discussion I had with my colleague who oversees a lot of these studies. It's hard to interpret. Both of us are agreeing that, at the highest dose, that 480-some milligram dose, that it may have been producing some adverse of the effects that volunteers just didn't like. And that's -- quite frankly, from an abuse potential perspective, that's great. But the most important thing is that there was a downturn and not an upturn in that question that for a lot of us is as valid as the liking scale, if not, more valid, and that's would you take this drug again.

Got it. And maybe just a quick follow-up. You mentioned those effects. Were there -- was there a bad drug effects, batch response that sort of came into play there?

We're going to be a -- oops, sorry.

We did have [indiscernible] yes, go ahead. No, Jack, please go ahead.

Yes. It's something we're discussing just this morning with the folks, that CRO that ran the study, and as you heard earlier, these -- we've looked at the most important findings that, that might help. As we get into that, it might help us better understand why those people didn't -- rated it lower on the highest dose. The most important thing, from my perspective, is that it's in contrast a classic drugs of abuse.

Yes, Ryan, we do have that end point as well. Sort of nothing to see there. So we didn't include it because there's a pretty low response overall for both nalbuphine and butorphanol. But the trend did go up. So with those, it got worse. It's just really low numbers. So I think to Jack's point, there's just some noise in this. This isn't a highly addictive drug, either of them.

And the next question is from Oren -- please proceed.

Just let me add a comment on butorphanol. There was a lot of discussion on what was the most appropriate control. And butorphanol itself is a messy drug. And it's not a great way to get high. So when you have a drug that people are selected to like it, again, you've got kind of an unusual population. So it's like having a -- you're going to test a new form of chocolate cake, and so you say you only get in the study if you really like chocolate cake. And almost everybody likes a little bit of what you're testing, and it's hard to understand sometimes. But again, that goes with the turf when you're dealing with relatively low abuse potential substances. And nalbuphine, by all measures, is lower abuse potential than butorphanol, but they're both in a muddy area compared to classic high abuse potential substances.

Our next question comes from Oren Livnat with H.C. Wainwright.

A lot to chew on here. I just want to talk a little bit more about the supratherapeutic dose. And clearly, there was not consistently higher liking there, which is great, across the secondary end points. I'm actually curious, looking at it from the other side of the equation. Since we -- I think most of us expected that to be less likable given the AE profile we've seen in some of your earlier data where we were starting to see more things popping up in a pretty clear dose response manner, is it actually potentially encouraging that perhaps in the real world, this drug is more tolerable than some of the tables might indicate from your prior studies if people managed to take this high a dose, 3x higher, and not have obvious deleterious impacts on their liking and their general status?

Yes. No, thanks for the question, Oren. I'm going to just give an overview. I got my trusty co-founder here who's a neurologist who I think will be more intelligent. I think what we heard about this study is this is an opioid experience subject. So you don't get these kind of AEs in people who are used to taking opioids. The brain gets tolerant to these adverse events, and you just don't see the kind of AEs overall. I don't know, Tom, anything you want to add?

Yes. I would say that the population, when you study a human abuse potential study population, these are people who, because of their past exposure to the substance of abuse that you're studying, which in this case is people who are opiate-experienced users, they're remarkably tolerant, and they really don't generate adverse events in any way at the rates that you would get in so-called populations of subjects that, for instance, the IPF or RCC subjects where you see adverse events that happen at higher rates. It's remarkable how low the adverse event incidence is and how less severe the adverse events are in the study population. So they can, as a result, can tolerate larger doses, and that's clinically consistent with what seasoned practice. When you're dealing with people who are in chronic pain, say, from cancer and you're essentially managing their care, you can essentially dose these people with very large doses over time, as you increase the dose as the pain increases. So people can tolerate large doses of opioids if you basically have a history of being exposed to an opioid. So it's not really a great population to sort of make assessments about the adverse event risk of the drug. You really are studying very focused questions that are around the abuse potential of the drug.

Okay. And I know you sort of touched on this from several different directions, but I guess, ultimately, you made it quite clear this is sort of a holistic conversation and evaluation the FDA and the DEA are making, right? They're not looking at one end point whether it's primary or secondary here, right? But overall, when it comes to the HAP data, whatever their takeaway is from it, relative to the other real-world findings like surveillance, diversion, et cetera, is there any sort of waiting and importance that this gets higher or lower than those other data such that whether it's oral or injectable, aside from that issue, just whether they have strong feelings about potentially rescheduling this thing, that this could play a major factor in that or not? Sorry if I was rambling there.

No, I get it. I think, Jack, I'll let you answer this. I think the question was is there one end point here that's more important than the others. I mean your primary end point's always important, but I do think they look at sort of the overall picture here. But I'll let you comment on that because you've witnessed this more than we have.

Sure. If, for example, liking and other measures showed a robust classic abuse increase -- linear increase in scores, that would have been -- that would have -- FDA would take that much more seriously than I think they will take this. And again, the increase at the triple high dose was only about 6 points higher. I mean it still pales by comparison to what we would have expected if this was an oxycodone-like drug. So -- but we didn't see that. So what would be an important factor? An important factor would be high risk of overdose. Well, we don't have that with this because it's a partial agonist, and we've got 4 decades of experience. So conversely, when you're trying to address the opioid overdose crisis, moving people away from opioids that are -- those types of opioids is a public health benefit. It's hard to sort them out, but there's going to be, I think, a number of factors that are going to be considered that I think are -- bode well for nalbuphine quite frankly.

If I may also, just that reminded me, earlier in the call, you mentioned the, I guess, disputes perhaps between the FDA and the DEA on tramadol where the DEA came out on the more draconian side, and maybe there were some unintended consequences to them pushing more people into the street opioid market for example. Do you think that that's a learning experience that weighs on both FDA and DEA decisions going forward? Is it possible that the FDA, having also gone through that, know what they're dealing with perhaps on the DEA side, would even further temper their recommendations if they believe the benefit/risk for this merits an unscheduled drug?

The FDA and DEA, they're people too. They're trying to do the same thing we all are, get it right. And the answers are not always simple. Similarly, up scheduling the -- I'm just going to call it the Vicodin category, the low-dose hydrocodone, APAP. FDA's argument was you're taking away something and will drive more people to Schedule II drugs. Whether that contributed to the overdose crisis, we don't know. But most recently, in 2020, FDA presented data, and they followed it up in 2022 at the College on Problems of Drug Dependence, listing 6, 7 drugs. The 3 DORA insomnia drugs, lacosamide and some antiepileptic drugs that were all overly restrictedly scheduled on the basis of HAP findings. And the FDA is now at its CCALC cross-company consortium meeting last fall, fall 2023, addressed what they're doing to do a better job of designing and interpreting HAP studies in the category of substances that are relatively low abuse potential. So I think there's a lot of learning going on, and I think it's going to make the FDA, I think, more careful than before. And that's not to say they haven't been careful. It's -- they're trying to get it right. But when you schedule something over restrictively such as the, and I published on this, the DORAs and now the most commonly prescribed substances for insomnia is trazodone, which carries much higher risks than the DORAs, FDA missed an opportunity with hindsight, who have left the DORAs unscheduled. So I think the FDA is working, tries to do its best and I think generally gets it pretty close to right. We're generally in pretty close alignment, but it's not simple. And sorry for the long answer. I wish it was simple, but I think all of this, quite frankly, bodes well for nalbuphine because I think FDA is going to consider the whole picture, all of these factors, and in the end, we'll be asking if there's there sufficient evidence to justify scheduling something that has not been scheduled since 1977 and has not been the source of a public health problem.

Jack, that was a great close, and we're upon our hour. Oren, thanks for your questions. So thanks to everyone for joining our evening call. I know we cut into your night. This marks the beginning of a really data-rich period for the company, and we're all looking forward to that. As I mentioned, we will be reporting out the results of the SSRE and our IPF chronic cough trial in the coming weeks. And we're available tonight for any follow-up questions you may have. Please send either Lisa or me an e-mail, and we'll get back to you and set up a call. Thank you for your time.

Thank you. The conference has now concluded. We thank you all for attending today's webcast. You may now disconnect your lines and have a wonderful day.