Welcome to the Trevi Therapeutics webcast, presenting the top-line results from the Human Abuse Potential, or HAP, study. At this time, all participants will be in listen-only mode. If you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your phone. To withdraw your question, please press star then two. Please note this event is being recorded. Various remarks the 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 factor 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, and 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 was developed in the 1970s to address a growing drug abuse problem. Nalbuphine, specifically, is a kappa agonist and mu antagonist, or gamma. This is important for several reasons. First, the DEA noted in its review of nalbuphine that its potent mu antagonistic effect can precipitate drug withdrawal in opioid-tolerant patients, so it is not likely that drug addicts would seek out nalbuphine if they are taking other opioids.
Second, the two 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 by 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 three 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 happ y 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 endpoints. This was a randomized, double-dummy, active, and placebo-controlled five-way crossover study. Subjects were recreational opioid users and first entered a qualification phase where they had to pass two 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 opiates. 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 five double-blind, double-dummy treatment arms and were given an IV and oral solution at each dosing day. There was a minimum four-day washout period between each of the five 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 endpoint 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 endpoint analysis was based on the peak drug-liking VAS, or VAS Emax, for each of the treatment arms. The first analysis to discuss is the 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 endpoint analysis in regard to drug-liking of three doses of nalbuphine as compared to butorphanol. We are very pleased that both doses of nalbuphine that were used in our clinical program, that is, the 81 mg and the 162 mg doses, demonstrated a statistically significant lower drug-liking response compared to butorphanol.
For the FDA guidance, we studied a supratherapeutic dose of 486 mg of 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 mg - 60 mg in our chronic cough clinical studies. Consequently, in this study, we tested a dose that was three times the highest clinical dose tested in our clinical program. In summary, with regard to the primary endpoint, 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 endpoints in this study in which the subjects 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 endpoint is represented by the VAS response to the statement, "At this moment, I feel high."
Note that this endpoint 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 mg and 162 mg doses rated at about half the feeling high ratings of butorphanol. These data are consistent with the primary endpoint findings. There is a similar story with another secondary endpoint using a unipolar VAS in which the subjects respond to the statement, "At this moment, I feel good drug effects." Once again, there were lower scores for nalbuphine across all doses, with the 81 mg and 162 mg 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 one piece of an overall eight-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 eight factors support keeping nalbuphine unscheduled. Public health risk is a critical aspect of the eight-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 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 a 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 risks 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 re-estimation, or SSRE, in our phase II-B CORAL IPF chronic cough trial in the next two weeks.
We expect to have the top-line results from our phase II-A 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 into 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 cough-related disorders. I've been advising on the 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 three decades of experience, or more than four 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.
Thank you. And just as a reminder to ask your question, you may press star then one on your touch-tone phone. If you're using a speakerphone, we ask that you please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Due to the number of participants on the call, questions will be limited to two per caller and any relevant follow-up to your question. If you have other questions, you may get back in the queue. Today's first question comes from Faisal Khurshid with Leerink Partners. Please go ahead.
Hey, everyone. Thank you for the time today. 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 HHS think about that supratherapeutic dose level?
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 mg and the 162 mg, 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 two 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 take this drug again. Even though that's officially a secondary endpoint, 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, "Wow, 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.
Yeah. 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?
So, 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. First, what we call bifurcated or trifurcated scheduling is extremely rare. The so-called Vicodin category of low-dose hydrocodone and acetaminophen was removed to parents relation schedule in 2014. So scheduling is generally by law and in practice based on the substance, not the form, and not the indication. That's part of the reason that FDA is generally reluctant to put them in different categories.
Yeah. I guess my question was more from a commercial perspective. For the Trevi management team, 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, and 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 2 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.
That's helpful. Thank you.
Thank you, Faisal.
Thank you. And our next question today comes from Leland Gershell with Oppenheimer. Please go ahead.
Great. Thanks for taking the questions. Yeah. 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 have 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?
Gosh, there's a number of different kinds of precedents over the many years, but I'll give you an old one. Nicotine gum in the past 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, some people said, FDA should recommend scheduling. And in the end, FDA did what it usually does, which is it kept it all in the same schedule. So it's rare that there are differences. In terms of adding something to the Controlled Substances Act 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 its 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 in the Controlled Substances Act. And again, that would be unusual, to say the least.
All right. Thanks very much for taking the question.
Thank you, Leland.
Thank you, and our next question today comes from Annabel Samimy with Stifel. Please go ahead.
Hi. 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.
Yeah. 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 significantly 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 one aspect of the eight-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 eight-factor plans, so I'll let him hear it from you.
Sure. And one of the most important aspects of the eight factors is the public health are the public health factors, and those are factors four, five, and six. And public health goes both ways. And the first way is, is there a public health threat related to the substance that essentially requires or warrants scheduling? And we've never seen that from nalbuphine. So that's factors four, five, and six. Nalbuphine is about as clean as it gets on that scope. Conversely, there's the potential public health benefits, which if we were working on the eight-factor, we would work in, and that is the benefits of shifting people away from Schedule 2 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 non-clinical measures. So all of this comes into play. The HAP study is one factor or one study and one factor. And for new chemical entities, if there are robust findings and more robust than we see here suggesting abuse potential, then in the past, FDA was more likely for 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 antagonist. They were scheduled on the basis of a HAP, and a few years later, just the last couple of years, FDA has basically said in two 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. And by the way, the term FDA often uses is, is there meaningful abuse potential, meaningful enough to warrant scheduling?
Great. Thank you. That's helpful.
Thank you, Annabel.
Thank you. And our next question comes from Deb Chatterjee with Jones . Please go ahead.
Hi. Do you hear me?
Yes. We can hear you.
Okay. Great. Thank you so much for taking my question. So could you maybe clarify one thing for me? So you mentioned that there should be an 11-point difference to be a meaningful morphine likability between the two groups. Is it the same for the primary as well as all the secondary endpoints?
No. Thanks for the question, Deba njana . So the 11-point reference is only to placebo in the stats thing. So it's not relevant to the butorphanol comparison or all the other secondaries. It's only to the placebo, and it's not relevant to the secondary endpoints. It was really just that comparison.
I see. Is there a threshold based on which the FDA or the DEA might consider what is more likable compared to butorphanol, even if that's not statistically significant?
So the two 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 we'll 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 where 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 this study.
They look at the totality of the data, and they look at that in the overall look at the eight-factor analysis.
Okay. Thank you so much.
Thanks, Debanjana .
Thank you. And our next question today comes from Serge Belanger with Needham & Company. Belanger, I'm sorry, with Needham & Company. Please go ahead.
Hi. Good afternoon. I guess the 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 the status quo or contemplate schedule changes? Would that be when you submit an NDA, or would that be part of discussions in a phase II meeting? And then.
Yeah. Oh, go ahead, Serge. Finish your question.
Sorry. 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. There won't be a final determination until the NDA is 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 a CSS consultant or in the phase two 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.
Yeah, 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 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 FDA and DEA disagreed, quite frankly. And FDA made the argument that the world really needs a non-scheduled pain reliever despite some abuse, and diversion, and overdose. And some people have argued that scheduling tramadol, which was pretty much pressured by DEA, it's hard to. There's no simple answers to the opioid overdose problem, but there were a lot of people that were getting adequate pain relief with tramadol that then turned 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 four decades.
By the way, Cara's drug was mentioned. I can disclose because I co-published 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.
Thanks for the additional color.
Thank you, Serge.
Our next question comes from Mayank Mamtani with B. Riley Securities. Please go ahead.
Yes. Good afternoon. Thanks for taking the questions, and appreciate the level of transparency here. So maybe for Dr. Henningfield, just to follow up on the secondary endpoint, take the drug again. For butorphanol versus placebo separation here, it seems small. How should we think about the clinical relevance of this endpoint 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 endpoint, and then I have a follow-up.
Sure. With drugs that are relatively low abuse potential and comparators that are relatively low abuse potential, 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.
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 over-sensitive. 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. 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.
Thank you. 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 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 the 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 three planning and obviously the studies you need to do for NDA planning? Thanks for taking our questions.
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 this study.
Yeah, 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 a CNS active drug, but there's really nothing that would make us alarm 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 development.
No. So for the SSREs, nothing here. I mean, this is actually validating. I think that I feel very positive about these drugs that validate sort of the thesis. I 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 you know 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.
Looking forward to that too. Thank you.
Thanks, Mayank.
Thank you. Our next question today comes from Brandon Folkes of Rodman & Renshaw. Please go ahead.
Hi. Thanks for taking my question, and congrats on the results. 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 and 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?
Yes.
Jack, I'll let you take that. Yes.
I'm sorry.
Is Jack going ahead?
What's the second 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?
Yeah. So it plays in two 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 four decades of experience, diversion from hospitals of drugs that are considered good drugs to get high on and good drugs to get liking, etc., they're diverted.
And the United States seems to be the canary in the mineshaft of trying to find out creative ways to abuse just about anything that's out there that seems to be a good way to get high and euphoric. This over four decades has not emerged in that category. I think FDA, out of an abundance of cautions, as I often heard from them, said, "Well, you're going to make the tent bigger with an oral form, and we want to look at that oral form. We want you to look at it with a HAP study.
Thank you very much, 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 tranche of data to be in IPF and also our RCC data, and we'll continue to dig in. Farrell, my commercial guy's waving me down. Farrell, just chime in here.
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 a category, right? It's benign to them. It's really prescribers. And in both of those categories, we don't see an impact.
Yeah. 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 yeah, a lot of room to move in IPF.
Great. Thank you very much.
Thank you, Brandon.
Our next question comes from Ryan Deschner, Raymond James. Please go ahead.
Hi. Thanks for the question. Was pupil dilation measured, and if so, was that response in line with the primary endpoint 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 offhand 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 can comment on that.
I don't have anything about that.
No. I don't have anything 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 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. Thank you. 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 as differentiated from overall drug liking? And what is your interpretation of the inverted response? Thank you.
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 mg dose, that it may have been producing some adverse effects that the 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, "What do you take this drug again?
Got it, and maybe just a quick follow-up. You mentioned those effects. Was there a bad drug effects VAS response that sort of came into play there?
We did have a question.
We're going to be looking. Oh, sorry.
Yeah. Go ahead. No, Jack, please go ahead.
Yeah. Yeah. It's something we're discussing just this morning with the folks at Celerion that ran the study. And as you heard earlier, we've looked at the most important findings, but that might help, as we get into that, it might help us better understand why those people rated it lower on the highest dose. The most important thing from my perspective is that it's in contrast to classic drugs of abuse.
Yeah. Ryan, we do have that endpoint as well. Sort of nothing to see there. We didn't include it because there's a pretty low response overall for both nalbuphine and butorphanol. But the trend did go up. With dose, it got worse. It's just really low numbers. I think to Jack's point, there's just some noise in this. This isn't a highly addictive drug, either of them.
Got it. Thank you very much.
Yeah. Thank you for the question.
Our next question comes from Oren Livnat. Oh, 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.
Thank you, Jack.
And our next question comes from Oren Livnat with H.C. Wainwright & Co. Please go ahead.
Thanks. 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 endpoints. I'm actually curious, looking at it from the other side of the equation, since 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 manage to take this high a dose, 3x higher, and not have obvious deleterious impacts on their liking and their general status?
Yeah. No. Thanks for the question, Oren. I'm going to just give an overview, but I've got my trusted co-founder here who's a neurologist who I think will be more intelligent. And I think what's weird about this study is this is an opioid-experienced 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?
Yeah. 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 this study population. So they, as a result, can tolerate larger doses. And that's clinically consistent with what's seen in 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've sort of touched on this from several different directions, but I guess ultimately, you've made it quite clear this is sort of a holistic conversation and evaluation the FDA and the DEA are making, right? And they're not looking at one endpoint, 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, etc., is there any sort of weighting 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 feel like you answered this. I think the question was, is there one endpoint here that's more important than the others? I mean, your primary endpoint'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. 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 six points higher. I mean, it still pales by comparison to what we would have expected if this was an oxycodone-like drug. 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 four 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 bode well for nalbuphine, quite frankly.
If I may, also, just that reminded me earlier in the call, you mentioned the, I guess, dispute 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 that and 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 and 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, upscheduling 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 six, seven drugs: the three DORA insomnia drugs, lacosamide, and some anti-epileptic drugs that were all overly restrictedly scheduled on the basis of HAP findings.
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. I think there's a lot of learning going on, and I think it's going to make FDA I think more careful than before. That's not to say they haven't been careful. They're trying to get it right. But when you schedule something over-restrictively, such as the, and I've 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, to have left the DORAs unscheduled. I think 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 I'm 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, is 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 email, and we'll get back to you and set up a call. Thank you for your time.
Thank you. The conference is now concluded, and we thank you all for attending today's webcast. You may now disconnect your lines and have a wonderful day.