Relmada Therapeutics, Inc. (RLMD) Earnings Call Transcript & Summary

Greetings. Welcome to Relmada Therapeutics Corporate Update Call. [Operator Instructions] Please note this conference is being recorded. At this time, I'll now turn the conference over to Tim McCarthy with LifeSci Advisors. Tim, you may now begin.

Thank you, operator, and thank you all for joining us this morning. As Slide 2 states, please note that certain information discussed on the call today is covered under the safe harbor provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, Relmada's management team will be making forward-looking statements. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in Relmada's press release issued today and the company's SEC filings, including the annual report on Form 10-K and subsequent filings. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, July 27, 2021. Relmada undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Now I'd like to turn the call over to the CEO, Sergio. Sergio?

Thank you, Tim, as always, and good morning to everyone. I'm Sergio Traversa, the Co-Founder and CEO of Relmada, and I have the pleasure to chair this call to welcome everyone to the conference call to discuss the topline results for the Human Abuse Potential, or HAP, study of REL-1017 versus oxycodone. On Slide 3, you will see a brief agenda for today's call. As an opening remark, we are fully aware that the reason there was an investor concern about the potential for abuse of REL-1017 due to the relation with the parent -- well-known parent drugs. There is considerable data already published that indicated that REL-1017 does not carry abuse risk, including a very clear statement from DEA, the Drug Enforcement Agency. However, we take your concern always very seriously. And we worked on the subject, executing animal and now human studies, evaluating the potential for abuse risk of the drug. This is a highly specialized field, and we worked closely with expert in this area that helped us and will continue to help to bring these projects to completion. Some of these experts are here today with us on the call and will be able to answer any questions related with knowledge and a lot of experience. That's why we asked Jack Henningfield to present the detail today. Jack is from Pinney Associates. He's a world-renowned expert in the field of abuse potential and he was instrumental in designing the HAP study. And he has, I believe, 40 years of experience in running abuse clinical studies. And he's also the former Chief of the Pharmacology Research Branch, the Abuse Potential and Biology of Dependence Assessment Section of the National Institute of Drug Abuse, the NIDA. And he's an adviser to Relmada. Following the presentation, we will open up the call for your questions. And we'll be joined by 3 very experienced gentlemen doctors in the field of abuse: Dr. Charles Gorodetzky, who is the former Director of the National Institute of Drug Abuse, the NIDA, and the research center in Lexington, Kentucky. Dr. Frank Vocci is former Chief of the Abuse Staff at the FDA and former Director of NIDA Medications Development Program. And Frank Sapienza, former Chief, Drug and Chemical Evaluation section of the DEA Office of Diversion Control. They will be able to provide a very peculiar and particular perspective from the agencies that regulate the controlled substance area: the FDA; the National Institute of Drug Abuse, NIDA; and the DEA, as they all cover high position at these agencies. With no further delay, I will now turn the call over to Jack, and he will review the study design and the results. Jack?

Great. Thank you. Can you hear me?

Yes, very clear.

Wonderful. It's a pleasure to be with you today and especially, with my long-term colleague, Drs. Gorodetzky and Sapienza and Vocci. Let me begin with a few comments on HAP studies and why they are a big deal in abuse potential assessment. Simply stated, the HAP, or abuse potential study, is the single most predictive and important type of abuse potential study that we do. The basic model is to bring recreational substance users into the laboratory to have them rate the effects of the test drug under double-blind conditions against placebo and a positive control. They are sort of like the Robert Parker wine connoisseur in the wine world. They're experts, if you will. This study was designed following FDA's 2017 guidance, Assessment of the Abuse Potential of Drugs, with input from FDA staff as well as me and other external experts in human abuse potential assessment. Following the guidance, a leading contract research organization with experience in these studies screen recreational opioid users for safety and scientific reliability. That included a naloxone challenge test to confirm that subjects were not physically dependent. Screening also included administering placebo and 40 milligrams of oxycodone before the study began. And this is to make sure that: first, this drug is safe to give; and second, to assure that the subjects were qualified for sensitivity as the FDA recommends. Following FDA's guidance, if they do not rate 40 milligrams of oxycodone with a score of at least 65 on the scale and at least 15 points higher than placebo on the drug liking scale, they were not qualified. These and other FDA recommended study details maximized sensitivity and accuracy. They make such studies generally more likely to overestimate abuse potential than to underestimate abuse potential. And that is reassuring to regulators, as I'm sure my colleagues on this line can tell you. So let's turn to the next slide to see more details of this study. So the primary measure was drug liking at multiple time points. Drug high and take again the drug. In other words, ratings of when you take the drug again are secondary measures and that is typical of such studies. Of course, there are a variety of other measures of behavior and physiological effects that we will not be discussing today. The basic design was a single-dose, randomized, double-blind, double-dummy, active, placebo-controlled, 5-way crossover. 40 milligrams of oxycodone was the positive controlled drug, and that is the most common drug recommended by FDA for such studies. 3 doses of REL-1017 were tested: the 25-milligram daily therapeutic dose; then a 3x higher dose, which is 75 milligrams; and then somewhat unusually, quite frankly, is a 150-milligram super therapeutic dose. That was 6x the therapeutic dose and that was possible because it was safe, and it is pushing the dose in such a study. 44 subjects completed all 5 treatment phases. The primary end point is Emax for drug liking, that is at this moment. And that is assessed by a bipolar scale from 0 to 100 with 0 is most negative, 50 is neutral and 100 is most positive. And again, this is a pretty common scale and recommended by FDA. So now let's get to the fun part, the data. The first slide -- I'm going to show you 2 data slides. And what we see is the primary end point, drug liking at this moment of REL-1017 versus oxycodone. Now Emax, or the highest drug liking, is shown across the treatment arms. Note that the mean and median for Emax across all treatment groups is statistically -- and the statistical significance and all treatment arms, including placebo and REL-1017 doses are highly significantly different from oxycodone. And that was true at all of these key time points. The standard deviations and standard errors are relatively low, and they demonstrate consistent and relatively tight clustering of ratings. Note that the 20-point difference between even the highest dose, the 150-milligram REL-1017, as compared to 40 milligrams of oxycodone. Thus, in my opinion, well -- and what the data show is that the primary end point did not show evidence of abuse potential. Also important for those of us that do these studies is the shallowness of the dose response curve compared to most drugs of abuse with only a small increase at the 6x therapeutic dose. Let's look at the next slide, and this compares REL-1017 to placebo statistically. And what you see is the median values for liking scores for REL-1017 at 25 milligrams and 75 milligrams are the same as placebo. By the way, in most of these studies, FDA recommends a 2 to 3x higher dose than therapeutic. So at the 3x higher dose, that also looks like placebo. The therapeutic doses do not significantly differ from placebo, and they are statistically equivalent to placebo for the primary end point. As expected for CNS-active drugs, 150 milligrams of REL-1017 did differ from placebo and showed a low-level liking. And by the way, what we find in HAP studies of CNS drugs is it seems that just about any CNS-active drug will elicit some kind of low-level bump in liking when tested at super therapeutic doses. Although for many drugs that we look at, it's much higher and sometimes overlaps with oxycodone. Note that the 150-milligram difference from placebo is actually slightly lower -- slightly below FDA's minimum dose to qualify for the study if you were a subject. Also keep in mind that 150 milligram is considered the maximum tolerated dose because this is the point that nausea and other side effects kick in, and they are dose limiting. By the way, there were other measures like global overall liking scores and ratings of taking the drug again. And they showed similar patterns and these further strengthened the results of this study, showing no evidence of meaningful abuse potential. Now let's get to the last general summary slide. And I just want to make a few summary points that's on the slide and a couple more. First, all REL-1017 doses showed highly statistically significant differentiation versus oxycodone. REL-1017 doses were not significantly different from placebo at the therapeutic range and the 3x therapeutic. The key secondary end points are consistent with the primary end point, and we look forward to showing those to you at some point but not today. By the way, these findings are consistent with DEA's current statement on methadone. And as the Drug Enforcement Administration states, the d-isomer lacks significant respiratory present action and addiction liability. And let me add a couple of other thoughts. First, my conclusion is that the primary outcome measure does not provide evidence of abuse potential. The results of this study, in fact, are in the range of what I have seen for drugs that include nonscheduled drugs as well as Schedule V and Schedule V drugs. So we don't know how this will be scheduled, but this is the range that this looks like to me. So at this point, we can conclude that REL-1017 does not produce subjective effects that are similar to a conventional opioid. Now we've got Drs. Gorodetzky, Sapienza and Vocci, and I think they can offer their own opinions of how these data will fit into the FDA and DEA drug scheduling assessment. So with that, I will turn the call back to Sergio. Sergio?

Thank you very much, Jack, for the great presentation. And as a reminder, this HAP study, it is an important opportunity to add to the already existing strong body of literature that I would say clearly differentiates REL-1017 or any potential perceived association with opioid effect, as Jack just stated. And this data will be part of the plan NDA, new drug application, submission for REL-1017 as a treatment for major depression. At this point, I would open up for questions. Operator, can you please open up the line for questions?

[Operator Instructions] And our first question is coming from the line of Andrea Tan with Goldman Sachs.

Congratulations on the data today. Sergio, maybe a question for you here. Given the profile of 1017 that you observed in the study, where those mean Emax scores are in the 50, 60s, just wondering if this increases your confidence in the outcome of the upcoming ketamine study. And could you just remind us where IV ketamine liking scores fall on the vast scale? And then I have a follow-up question.

Thank you, Andrea. And well, I will leave the second part of the question to some of other experts. And the first one, if these data will make us more comfortable and confident in the outcome of the ketamine study, well, let me tell you, point number one, the ketamine study is a lot less important than the oxycodone because the concern was not about -- the psychotomimetic profile that we've already seen is not there, but it was more on the narcotic and that I do believe this data will clear the path. But yes, I assume that drugs do not change behavior dramatically. So whatever we have seen in terms of likability in this study, I would say, most likely, it will be similar to -- in the ketamine study. I hope I answered your question in the way you expected. And the second part, I will let some of the experts to comment.

This is Frank Vocci. I would say that the 25- to 75-milligram doses were essentially indistinguishable from placebo. So I would expect the same here. You're going to have -- and the ketamine study is essentially a similar design where it's a crossover, everyone gets all doses. And what I would expect is that ketamine is going to give a rating on the Emax liking well above 65%. And we're going to be in the -- somewhere in the 50s with the REL-1017. So I would expect essentially similar results. And I would think that this would help to buttress the idea that this drug has either low or absent abuse potential.

Great. And then maybe just a follow-up there for you, Dr. Vocci or Dr. Henningfield. Just curious if you're able to comment on the path or process to getting a drug unscheduled.

Well, this drug -- Jack, do you want to go?

I missed the last part of that. Could you speak a little bit more slowly?

Sure. Just wondering if you're able to comment on the path or the process to getting a drug unscheduled, pending the completion of these studies?

Well, the key thing will be in the new drug application submission will include an abuse potential assessment and that typically includes an 8-factor analysis even though it's not required. And that will make the recommendation to FDA based on all lines of evidence. And I can't overestimate the fact that it's all lines of evidence that will be considered. FDA then will make the ultimate decision, the ultimate key recommendation. And by law, the improving transparency in therapeutics act of 2015, DEA will be required to follow that within 90 days unless they have a good reason not to. And Frank or one of you, I don't think that changes when the recommendation is for decontrol. The law pertains to what the schedule should be. This is a little bit different. So maybe one of you can comment on that.

Yes. This is Frank Sapienza, formerly from DEA. So the sticking point with this substance is that methadone itself, including both isomers, the D and the L, which would include the 1017 isomer, is also controlled under an international treaty. And the United States is obligated to follow those international treaties. So it's highly likely that REL-1017 would have to be scheduled somewhere. Now with the controls that are required internationally, DEA could satisfy those controls with anything in Schedule V or Schedule IV. They would not have to put it in Schedule II, which would be consistent with what this study shows also. So if HHS came over to DEA and recommended decontrol, DEA would have to evaluate that against what the international treaties require. And it's highly likely that they would say, "Well, no, we can't do that because of international treaties at this time," unless at some point, someone petitioned the WHO, the World Health Organization, to decontrol it. But that's why -- one of the main reasons why I think we think that although this would not be a Schedule II, it would probably end up being scheduled somewhere in one of the lower schedules.

This is Chuck Gorodetzky. I will add to that as well that, so far, the data looks like it is consistent with something that would probably be in a Schedule IV or Schedule V, which both Frank and Jack have noted. I think that we're looking at the shallow dose response curve, the essentially similar if not identical to placebo, at both the therapeutic dose and the 3x therapeutic maintenance dose, which is the initial dose and even the very small increase that we see when we go to 6x the maintenance dose. So I think this very much looks like it should be somewhere in the lower schedules like a IV or V.

And this is Henningfield. Let me add a point to that. When -- this will be a new chemical entity, for all practical purposes. I mean it's in -- it's a funny area. But also, that makes FDA and DEA a little bit more careful and wanting to see real-world data. And so I think we're all in agreement that it's likely that it will be controlled, and then we'll see what happens in the real world. And we have a recent example of the Epidiolex CBD, which was placed in Schedule V and then removed. Whether this would ever be removed, we don't know, but it's going to depend a lot on what it looks like after it is marketed.

This is Frank Vocci. I agree. I think it would be a 2-stage process, probably IV and V. And then later with post-marketing data and the international control issue resolved, it could go unscheduled.

The next question is coming from the line of Joon Lee with Truist Securities.

Congrats on the highly positive data. Is the HAP study criteria that you conducted successfully and reported data on similar across different international regions, say, EU, for example? I'm just curious about the scheduling criteria in other regions where you may be looking to commercialize this. And you also tested the 6x dose, the 150-milligram dose. What does that do for you in terms of labeling discussions with the FDA and scheduling discussions with the DEA? And we're asking because are you -- our understanding is that you're required to test up to 3x the dose, but you went ahead and tested a 6x dose, which a lot of investors are curious as to the reasons why you're going above and beyond, if there's any benefit to having that data. And I have a follow-up.

This is Henningfield. Let me just comment on one aspect of that. There are a number of things there, but one aspect is the selection of the 150-milligram dose. And in planning this study, we had a lot of discussion. And my first recommendation, which was consistent with the FDA guidance, was 2 to 3x higher. The thing is the safety profile permits a higher dose. And quite frankly, it's more compelling to advisory committees and to FDA staff if you really push the dose as high as you can. I think some sponsors might have said, "Well, let's just go to 3x." I think the fact that they went to 6x makes the -- my confidence in the outcome stronger because they really pushed it. Any others want to comment on other aspects of that?

This is Chuck Gorodetzky again. I agree, Jack. I think that it certainly gives you greater confidence when you go to those higher doses. And I think it has -- routinely, the FDA has suggested, if not required, that doses that are somewhat super therapeutic be tested. And I think that gives us a lot of confidence that the abuse liability of this drug is very low.

Great. And then Epidiolex was moved along the DEA scheduling and then eventually not scheduled at all. Were there any concurrent uptick in adoption among your colleagues of this drug? If you're aware of any anecdotal evidence, would love to hear that.

Chuck? Frank? Frank, do you have any inside thoughts on that? Epidiolex showed very low abuse potential, but I think that everybody was probably a little nervous. And there are international considerations, as Frank Sapienza have noted before. I don't have any inside thoughts for you folks.

No, I don't.

Could you repeat the question? This is Frank Sapienza. I'm sorry, I missed it.

Yes, yes, yes. So Epidiolex moved along the scheduling and eventually was not scheduled at all. Was there concurrent uptick in prescriber adoption of Epidiolex? If you have any anecdotal evidence of that?

No, not that I'm aware of. I'm sorry.

I'm not aware of any, either. It's being tested in a number of different patient populations now by people under night at grants. I'm aware of that, but I'm not aware that the actual prescribing is -- has changed as a result of the control issue.

Yes. Joon, if I can -- Sergio here. If I can step in for a second, and I'll ask the advice of the expert. But in prescribing patterns for Schedule IV, V and nonscheduled, if you look at the market around, there don't seem to be another big difference. So there is no difference at all.

Got it. And then, Sergio, if I could add one more question, and this is not that related to those -- to these results. But you recently disclosed acquisition of psilocybin last week. I'm just curious what your strategy is there. I mean are you looking to develop this in depression as well? And if so, would this be a competitive thing versus esmethadone? Or are you looking to develop this as a complementary to esmethadone? I'm just curious what your strategy is there.

Yes. Thank you, Joon. We would like to focus this call on the data that we presented. But since you asked, I don't like to avoid questions, so no. Well, the -- mechanistically, psilocybin is a 5-HT2A antagonist. And it fits with the neuroplastic concept, the neuroplasticity that we are focusing on. And esmethadone, REL-1017, works with a similar -- or same goal with a different mechanism with this NMDA blocker. But the strategy there is complementary in terms of science. But for psilocybin, we are going for a totally different route. So we are going to neurology and neurodegenerative diseases, not Alzheimer, just to make it clear. But -- so it will be complementary strategically. But there is no really intention to develop psilocybin for depression or any psychiatric diseases, at least for now but probably for a long term. So it's neurology.

This is Jack Henningfield. I am working on psilocybin and other substances as well. And remember, we've got more than 17 million people with major depression in the United States, about 300 million worldwide. And what's really important about REL-1017 to me is that it is, relatively speaking, rapid acting. And it appears to have its benefits within days, not weeks, and that is really important. And so it's a drug that would be given every day like conventional antidepressants as far as I know. Sergio can comment. And that gives it a very important potential place. Psilocybin and other drugs have an equally important place, but it's a different model, a different treatment paradigm. And I think there's a lot of room for multiple products to help different kinds of people.

Our next question is from the line of Andrew Tsai with Jefferies.

Congrats on the nice data readout. So I have 2 questions. First one is just managing expectations here. Could we expect you to have any kind of, I guess, FDA interactions in the near term so we can have a better understanding of how they think about these results? Or should we expect that the next time you talk to the FDA to be, I guess, when you have a pre-NDA meeting? I figure you have a Fast Track, so that's why I asked.

Yes. Thank you, Andrew. I can take that question. We will provide as soon as we get the final report. We only got the top line for now. We get the final report with all the details we will provide to the FDA. And I do believe we'll probably have some impact on the future development. To be direct, the FDA has never really raised major issues about the risk of abuse. This data we are required for the NDA but not for running like 3 Phase III trials that are ongoing now. So -- but I would say that definitely, they will help. But we have a former FDA high officer on the call, so maybe Frank Vocci want to comment on this? The question is what this data will mean for the future and dealing with the FDA on the development.

Well, I think the study showed that even people who are sensitized to opioids and recognize them very well could not differentiate the regular therapeutic dose or the loading dose from placebo. So I think when I would predict that when you look at the totality of the data, including people and clinical trials who are not opioid sensitive or have not really been sensitized to what an opioid feels like, they're not going to find this to be opioid like. They're not going to find it to be pleasurable. So I think this is going to bode well for the safety profile and also the scheduling. I think the FDA is going to be very reassured that they're not going to be losing a drug on the American public, that it's going to turn out to have an abuse problem.

This is Henningfield. Let me just add, I mentioned before, scheduling is based on the totality of all of the evidence. And at the drug dependence -- College on Problems of Drug Dependence meeting, we presented 2 studies in animals. And one looked at the reinforcing or rewarding effects in the intravenous self-administration model and that found no evidence of reinforcing effects in routes. And the other looked at physical dependence withdrawal in a rat model. Now again, and that did not see evidence of withdrawal compared to morphine. Human data are the most important. There are -- the Phase III clinical trials, the adverse events will be important to collect and look at. So all of that will be considered, but right now, this is a pretty favorable-looking profile compared to a conventional opioid. And I can't overestimate Frank's comment on respiratory depression. That's a very scary thing, and everything we know is that the respiratory depressant effects are very small.

Great. So basically, you're saying it's all about the sum of totality of evidence, which everything is pointing in the right direction. And as I think about eventual scheduling, I mean I understand FDA, DEA, they weigh in this 8-factor analysis. And so I guess how should we think about the importance of this abuse liability study as well as a ketamine study relative to these other 7 factors? And just to be clear, I'd assume that the other 7 factors just stack up very favorably in your view. You're confident the other 7 factors are great, too.

Well, I think it's going to stack up favorably. The data here, we're not seeing any data in animals or in humans that gives us cause for concern. In fact, we're seeing data that's reassuring us that the therapeutic dose and the loading dose are essentially probably not going to be seen by anyone as being abusable. So I think that's very good. So the fact that the six-fold dose gave a slight indication that it is still right at the height of the placebo response rate, that's a very shallow dose response curve. And that also bodes well in terms of the consideration of where to go into schedule and also what kind of side effects one might get. You're at the maximum tolerated dose there, and it still didn't break out from placebo. So I think it's all very reassuring data that even though this drug comes from methadone and is one of the isomers of methadone, that it lacks the abuse liability of the racemic mixture.

This is Frank Sapienza. So in the world of scheduling, you have drugs that are in Schedule I and II and then you have drugs that are in Schedules III, IV and V. And from a practical standpoint, there's really 2 schedules: It's I and II versus III, IV and V. Drugs in Schedule I and II are very strictly controlled and regulated. And drugs in III, IV and V are much less strictly regulated and controlled. And I think this study clearly shows without any argument that 1017 does not belong in the Schedule II category at all. If anything -- and the totality of data will show this as well as the international treaty issue that if it is controlled at all, it will be in the lower schedules -- one of the lower schedules, which are significantly, significantly less restrictive than Schedule II. So I think the real takeaway from this is that it's not a conventional opioid. There's no way that it would ever end up in Schedule II, and it will most likely be in one of the lower schedules.

Fantastic. Really quickly, did you guys happen to capture AEs of special interest like euphoria, relaxation or even dissociation and hallucination? Can we expect the AE data down the road?

Yes. I hope that somebody, maybe Dr. Manfredi or Dr. Pappagallo, they have seen all the data. No, we are not aware of any particular AE. We would know if there was any issue related with that. But no, the study was not designed to detect these kinds of things. But if there was something that was spiking, clearly, we would have been told. But I'm not aware of anything. Paolo or Marco?

Yes, it's confirmed. I agree.

That's Marco.

This is Dr. Pappagallo. Yes, there were none.

And to add a follow-up, we are going to be presenting these data conferences, and we will have the full picture at that time. But no concerns about adverse event of special interest.

Our next question comes from the line of Jay Olson with Oppenheimer.

Thank you for hosting this call and providing access to the experts. It's super helpful to get their interpretation of these HAP study results. And it sounds like there's a consensus around Schedule IV or V based on these data. So I was wondering if -- Sergio, if you could please comment on how Schedule IV or V lines up with Relmada's expectations? And how that would impact the commercial opportunity for 1017? And then I had a second question if I could.

Yes. Thank you, Jay. Yes. I mean, look, we are discussing in the past, based on the evidence of the published data, which -- I believe Chuck Gorodetzky was involved in the early stage of his career, so he can comment on this. But the expectation was IV, V is a fair scenario, not because the drug should -- deserve to be controlled but because of the old process of descheduling a drug. So straight answer is yes, they are perfectly in line with our expectation and with what the previous data they have shown. And Chuck, do you want to comment on that from the old data?

Certainly, I can comment briefly on the old data. There were 2 early studies done at the Addiction Research Center. One in -- It was done around 1946, published in 1948. That was just after methadone was brought to the United States after World War II, and the other was published in 1962. It arrived at the Addiction Research Center in 1963. I was not involved specifically in those studies but certainly was involved with the investigators, primarily Harris Isbell and Frank Fraser. And certainly, we're familiar with the methodology. In basic summary, the data is certainly consistent. The old data certainly at these dose levels would indicate very little in the way of opiate like. At very high doses -- and somehow, they got to very, very high doses, up as far as 1,000 milligrams. But even at those doses, there was a lot of disliking, a lot of negative effects. And although it did have some indication of opioid-like activity, patients -- and these were very small numbers. They did something like only 5 patients in these -- in the critical study that was reported in 1962. They -- still, the conclusion was very low abuse liability. So I think that what we're seeing in the new data is much better. The methodology, of course, has been much improved from what was done in the '40s, certainly, and even in the '50s and '60s. The methodology has developed quite a bit and much more sophisticated now, including statistical analysis, including the way the questions were awarded, the kinds of scales that were used. And I would put a lot more credence on today's data than I would on data that was gathered in the late 1950s, early 1960s. But even then, it's consistent data. Certainly at the lower doses, there was nothing in the original study in 1948. They found nothing, went up to 90 milligrams and found no evidence of any opiate-like effects at all. And the overall conclusions are very consistent with what the data we see now.

Great. That's super helpful. And then separately, I was wondering if the experts could share their thoughts on the human abuse potential of psychedelic compounds. And specifically, what level of scheduling would they expect for psilocybin?

This is Henningfield. I published with Roland Griffiths and colleagues at Johns Hopkins an 8-factor analysis. Now that's not -- this is premature. The NDA hasn't been filed. A lot of data are to be gathered yet. But my main conclusion is that it does not look like a Schedule II drug. In our paper, we said, based on the data we had, it looks more like a Schedule IV drug. But again, that's premature. And I think the important point that Frank Sapienza made earlier is you can think of really 2 general categories of scheduling. II and above and -- or II and I and everything below. And if I just don't see anything about psilocybin that makes it looks like a Schedule II drug. Where we'll end up, we'll have to wait.

This is Frank Sapienza. I'll comment on necessarily where psilocybin should go. But hallucinogens in general were put in Schedule I primarily because they had no currently accepted medical use, which was a criteria for drugs in Schedules II, III, IV or V. So because they had an abuse potential, they automatically went into Schedule I. Now that we're seeing some of the hallucinogens, including THC, for example, Marinol being looked at for medical use, their abuse potential would be reassessed more realistically. And there's no reason why they couldn't or should go into schedules lower than Schedule II.

Our next question is from the line of Marc Goodman with SVB Leerink.

I guess, first of all, there were 50 patients that went into the study and 44 evaluated. Just can you talk about the 6 that were not? And in these HAP studies, is that a usual number of patients that are not evaluated? And why were they not evaluated? And then secondly, you kind of breezed through it by saying all the secondary end points were consistent. Is there any more color you can give us about some of the secondary end points? I mean to take the drug again, was -- I mean, was that very strong? Were all of these basically exactly the same with respect to the primary end point as far as the [indiscernible]?

I'll comment on the size and maybe Sergio can comment more on specifics of other end points. But for a registration -- FDA registration trial, this is pretty typical, a little larger than some. There are a few that are larger than this. For an academic study, those are usually 10 to 15. And Dr. Gorodetzky mentioned the Addiction Research Center, where I also was. Most of our studies were around 10 people.

Right. And Jack, maybe you saw the data. You may want to comment on the secondary end points that are in line with the primary.

Yes. The couple of the key ones that I look at are the overall, what we call, the global liking and also the ratings of will you take the drug again. And these -- I don't have the actual -- the numbers in front of me, but the patterns were very similar to liking. And that's important because every once in a while, we see a drug in which the liking -- acute liking is relatively low, but the total global is high. And people say, I would take it again and rate it highly. And we didn't see that here.

And with respect to the numbers, my question was 44, a big number of patients for the study. It was more of -- we started with 50, we ended with 44. And so what happened to the other 6? And is that typical with these HAP studies, for that percentage to kind of not be evaluated?

Yes. Marc, I can give you the top-down, and then Dr. Manfredi or Pappagallo can give you some more detail. But this is a special patient population. So I do believe that like 3 or 4, they just didn't show up. They had to come in 5 times. And if somebody does not show up for one time, then he's automatically excluded from the trial. And there were 2 or 3 that did not -- were not evaluable for the results. And these are people that don't recognize oxycodone. So they had a score of oxycodone like 50 or 70 for placebo or -- so it was purely technical. There was a very rigid criteria for inclusion/exclusion after the data were unblinded. And so there were, I believe, 2 or 3 patients that did not qualify for -- their result didn't make any sense. These are the 6 patients. No side effect, nothing that would be worrisome. It's pretty normal for this kind of study.

It's a pretty typical number. It's rare that out of 50 subjects, they all get through all conditions.

The next question comes from the line of Eddie Hickman with Guggenheim Securities.

This is Eddie on for Yatin. Could you talk about what the implications for the top dose being statistically different from the placebo are on liking even though it was different from oxy and sort of what that means? And then given these data, can you just sort of reset your expectations for the ketamine study on timing and sort of what you're looking for? And then for the experts, sort of what would be -- what would need to be seen in the ketamine study to imply a Schedule III? And sort of how would that change your thinking on things?

Thanks, Eddie. The first one, Jack, maybe you.

I didn't hear the first part of that, but I think either of the Franks would be great for the scheduling implications and maybe all of this question.

Yes, the first part was the implication of the difference at the maximum tolerated dose with placebo, what the implication can be. Could you...

Well, the main thing is, to my eye, it's a very small increase. It's a relatively shallow increase. And we have seen drugs where they were also fairly shallow dose response curves, and I published studies with some of these drugs. And then at the super therapeutic dose, there is a robust bump that comes closer, overlaps with oxycodone, and we didn't see that.

Yes. The high dose 150, if I recall correctly, the median was 58. So that basically tells you that 22 people out of 44 were between 50 and 58 and that the other 22 were above 58. But when you average them all together, they're at 64.9. So there is a range of people. And there is probably somewhere around 1 out of every 3 people recognize this as something that they liked but it was only that. And when you look at the mean score and the medians, they don't differentiate from placebo. So I think it's very reassuring that you're at a top dose there, 6x the therapeutic dose, and people are -- some people are barely getting some perceptible effects.

And even that -- this is Chuck Gorodetzky. Even at the 150-milligram dose, it's still pretty much similar to placebo. It would not be at p less than 0.001, but would be p less than 0.1. There is really not a big bump there.

And if you look at the median score for oxycodone, the median score for oxycodone was 89, I believe. So it's 58 versus 89. So you see that when you look at the medians, people are far more likely to recognize oxycodone as an opioid and score it very highly.

Got it. And then on the ketamine study, sort of how are you -- what are you expecting? And then like for the experts, sort of what would you need to see in that study that would imply a Schedule III?

My expectation will be a shallow dose response again for REL-1017 and that you would have to have something that exceeded that. That would essentially exceed my expectations that individuals who had ketamine experience found this to be nearly as pleasurable as ketamine. And I don't think you're going to see that, but I think that's what you'd have to see for a Schedule III.

I think it might also be important -- this is Chuck Gorodetzky. I think it might also be important when we look at the secondary measures, including what drug they identify it as. Do they identify it as a hallucinogen? Do they identify it as a sedative? Do they identify it as something else? I think that's going to be an important addition as well.

And then if we can help in the 44 patients evaluated in this study, we have not seen -- There is no report of hallucinogenic effect. So that looks in some ways an anticipation of what we should see on the ketamine study. And it's confirmed by the Phase I and the Phase II. Even at the maximum tolerated dose, this is not psychedelic or even close to psychedelic effect.

At this time, I'll turn the floor back to management for any further remarks.

Thank you, operator. And I think this concludes the call, and thank you all for joining the call today. Of course, we are very pleased with the results of this. I would call it confirmatory study. And those individuals suffering from depression are really in great need of something new, safe and rapidly effective treatment. And with these compelling results, I mean, increase our confidence in the ongoing REL-1017 late-stage development program. Based on the collective data that we have generated to date, REL-1017 has demonstrated significant potential. It's a new, novel, safe and fast-acting treatment for depression. We are excited about the catalyst important that lie ahead of us, maybe the Phase II and so on, and the ketamine study. And we'll keep you updated on clinical readouts and activity through the remainder of 2021. Again, thank you all for joining us. And I wish everyone to enjoy the rest of the day. Thank you very much, and thank you, our adviser, of course.

Thank you, everyone. This will conclude today's conference. You may disconnect your lines at this time. Thank you for your participation.