Greetings. Welcome to Relmada Therapeutics' corporate update call. At this time all participants are in listen only mode. A question and answer session will follow after the presentation. If anyone should require operator assistance during the conference, please press star zero from your telephone keypad. Please note that 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 two 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 of 1995. 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 27th, 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. I'd like to turn the call over to the CEO, Sergio. Sergio? Thank you, Tim McCarthy. As always, good morning to everyone. I'm Sergio Traversa, the Co-founder and CEO of Relmada, I have the pleasure to chair this call to welcome everyone to the conference call to discuss the top-line results for the Human Abuse Potential, or HAP, study of REL-1017 versus oxycodone. On slide three, you will see a brief agenda for today's call. As an opening remark, we are fully aware that there was an investor concern about the potential for abuse of REL-1017 due to the relation with the well-known parent drugs. There is considerable data already published indicating that REL-1017 does not carry abuse risk, including a very clear statement from the DEA, the Drug Enforcement Administration. We take your concern always very seriously, 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 work closely with experts in this area that helped us and will continue to help to bring this project 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 data 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 on Drug Abuse, the NIDA, and is an advisor to Relmada. Following the presentation, we will open up the calls for your questions. We'll be joined by three very experienced gentlemen, doctors in the field of abuse. Dr. Charles W. Gorodetzky, that is the former director of the National Institute on Drug Abuse, the NIDA, and at the Addiction Research Center in Lexington, Kentucky. Dr. Frank Vocci is former chief of the Drug Abuse Staff at the FDA and former director of NIDA Medication Development Program. Frank Sapienza, former chief, Drug & Chemical Evaluation Section at the DEA Diversion Control Division. 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 on Drug Abuse, NIDA, and the DEA, as they all covered high positions 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 colleagues, Doctors 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 connoisseurs in the wine world. They're experts, if you will. This study was designed following FDA's 2017 guidance Assessment of 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 screened 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 mg of oxycodone before the study began. This is to make sure that first, the drug is safe to give, and second, to assure that the subjects were qualified for sensitivity as FDA recommends. Following FDA's guidance, if they do not rate 40 mg 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 maximize 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. Let's turn to the next slide to see more details of this study. The primary measure was drug liking at multiple time points. Drug high and take again the drug, in other words, ratings of would 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, five-way crossover. 40 mg of oxycodone was the positive control drug, and that is the most common drug recommended by FDA for such studies. Three doses of REL-1017 were tested. The 25 mg daily therapeutic dose, then a three times higher dose, which is 75 mg, and then somewhat unusually, quite frankly, is a 150 mg super therapeutic dose. That was six times the therapeutic dose. That was possible because it was safe, and it is pushing the dose in such a study. 44 subjects completed all five treatment phases. The primary endpoint is Emax for drug liking. That is at this moment. That is assessed by a bipolar scale from 0- 100, with zero is most negative, 50 is neutral, and 100 is most positive. Again, this is a pretty common scale and recommended by FDA. Now let's get to the fun part, the data. The first slide, going to show you two data slides. What we see is the primary endpoint, drug liking at this moment of REL-1017 versus oxycodone. 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 in the statistical significance. All treatment arms, including placebo and REL-1017 doses, are highly significantly different from oxycodone. That was true at the 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 mg REL-1017, as compared to 40 mg of oxycodone. In my opinion, well, and what the data show, is that the primary endpoint 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. This compares REL-1017 to placebo statistically. What you see is the median values for liking scores for REL-1017 at 25 mg and 75 mg are the same as placebo. By the way, in most of these studies, FDA recommends a 2x- 3x higher dose than therapeutic. 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 endpoint. As expected for CNS active drugs, 150 mg of REL-1017 did differ from placebo and showed a low-level liking. 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. For many drugs that we look at, it's much higher and sometimes overlaps with oxycodone. Note that the 150 mg difference from placebo is actually slightly below FDA's minimum dose to qualify for the study if you were a subject. Keep in mind that 150 mg 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 take the drug again. They showed similar patterns, these further strengthen the results of this study, showing no evidence of meaningful abuse potential. Let's get to the last general summary slide. I just want to make a few summary points that's on the slide and a couple of 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 endpoints are consistent with the primary endpoint, 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. As the Drug Enforcement Administration states, the D-isomer lacks significant respiratory depressant action and addiction liability. 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 non-scheduled drugs, as well as Schedule IV and Schedule V drugs. We don't know how this will be scheduled, but this is the range that this looks like to me. 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. With that, I will turn the call back to Sergio. Sergio? Thank you very much, Jack, for the great presentation. 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 effects, as Jack just stated. This data will be part of the planned 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? Yes, thank you. At this time, we'll be conducting a question and answer session. If you'd like to ask a question, please press star one from your telephone keypad and a confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we poll for questions. Thank you. Our first question is coming from the line of Andrea Tan with Goldman Sachs. Please proceed with your questions. Thanks for taking the question. Congratulations on the data today. Sergio, maybe a question for you here. Given the profile of REL-1017 that you observed in this study, where those mean Emax scores were in the 50s, 60s, just wondering if this increases your confidence in the outcome of the upcoming ketamine study. Could you just remind us where IV ketamine liking scores fall on the VAS scale? I have a follow-up question. Thank you, Andrea. Well, I will leave the second part of the question to some of our experts. On the first one, if this data will make us more comfortable and confident in the outcome of the ketamine study? Well, let me tell you, the point one, the ketamine study is a lot less important than the oxycodone because the concern was not about the psychotomimetic profile that we already seen is not there. It was more on the narcotic, that I do believe this data will clear the path. Yes, I assume that drugs do not change behavior dramatically. 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. The second part, I will let some of the experts to comment. This is Frank Vocci. I would say that the 25 mg and 75 mg doses were essentially indistinguishable from placebo. I would expect the same here. The ketamine study is essentially a similar design, where it's a crossover. Everyone gets all doses. 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 somewhere in the 50s with the REL-1017. 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, 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, for this drug, Jack, you want to go? I missed the last part of that. Could you speak it a little bit more slowly? Sure. I was 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 eight-factor analysis, even though it is not required. That will make the recommendation to FDA based on all lines of evidence, and I can't overestimate the fact that it is all lines of evidence that will be considered. FDA will make the ultimate decision, the ultimate key recommendation, and by law, the Improving Regulatory Transparency for New Medical Therapies Act of 2015, DEA will be required to follow that within 90 days, unless they have a good reason not to. 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, maybe one of you can comment on that. This is Frank Sapienza, formerly from DEA. 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. The United States is obligated to follow those international treaties. 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. If HHS came over to DEA and recommended decontrol, DEA would have to evaluate that against what the international treaties require. 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. That's 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. I think this very much looks like it should be somewhere in the lower schedules, like a IV or a V. This is Henningfield. Let me add a point to that. This will be a new chemical entity for all practical purposes. It's a funny area, but also that makes FDA and DEA a little bit more careful in wanting to see real world data. 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. 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 two-stage process, probably IV and V, and then later with post-marketing data and the international control issue resolved, it could go unscheduled. Great. Thanks, everyone. The next question is coming from the line of Joon Lee with Truist Securities. Please proceed with your questions. Hi. Thanks for taking our questions. 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 in. You also tested the 6x dose, the 150 mg dose. What does that do for you in terms of labeling discussions with the FDA and scheduling discussions with the DEA? Only asking because our understanding is that you're required to test up to 3x the dose, but you went ahead and tested the 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. Thank you. 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 mg dose. In planning this study, we had a lot of discussion, and my first recommendation, which was consistent with the FDA guidance, was 2x-3x higher. The thing is, this safety profile permits a higher dose. 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 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. I think that gives us a lot of confidence that the abuse liability of this drug is very low. Right. As 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. Thank you. Chuck, Frank. Frank, 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 noted before. I don't have any inside thoughts. You folks? No, I don't. Could you repeat the question? This is Frank Sapienza. I'm sorry, I missed it. Yeah. As EPIDIOLEX moved along the DEA scheduling and eventually was not scheduled at all, was there a concurrent uptick in prescriber adoption of EPIDIOLEX? Oh. Yeah. If you have any anecdotal evidence of that. No, not that I'm aware of. I'm sorry. No. Thank you. I'm not aware of any either. It's being tested in a number of different patient populations now by people under NIDA grants. I'm aware of that, but I'm not aware that the actual prescribing has changed as a result of the control issue. Got it. Thank you. Yeah, Joon, if I can, Sergio here, if I can step in for one second and allow the advice of the expert. Yeah, in prescribing patterns for Schedule IV, V, and non-scheduled, if you look at the market around, there is really not a big difference, or there is no difference at all. Got it. Then Sergio, if I could add one more question in, and this is not that related to today's results, but you recently disclosed acquisition of psilocybin last week. Curious what your strategy is there. Are you looking to develop this in depression as well, and if so, would this be a competitive thing versus esketamine, or are you looking to develop this as a complementary to esketamine? Curious what your strategy is there. Thank you. Yeah. Thank you, Joon. We would like to focus this call only on the data that we presented. Since you asked, I don't like to avoid questions. No. Well, mechanistically, psilocybin is a 5-HT2A agonist, and it fit with the neuroplastic concept and neuroplasticity that we are focusing on, and esketamine REL-1017 works with a similar or same goal with a different mechanism. It is an NMDA blocker. The strategy there is complementary in term of science. For psilocybin, we are going for a totally different route. We are going to neurology and neurodegenerative diseases, not Alzheimer's, just to make it clear. 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 time. It's neurology. Got it. Thank you. This is Jack Henningfield. I'm working on psilocybin and other substances as well. Remember, we've got more than 17 million people with major depression in the United States, about 300 million worldwide. 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. That is really important. It's a drug that would be given every day like conventional antidepressants, as far as I know. Sergio can comment. 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. Thank you, Jack. Thank you. Next question. Yes, our next question is from the line of Andrew Tsai with Jefferies. Please proceed with your questions. Hi, good morning. Congrats on the nice data readout. I have two questions. First one is just managing expectations here. Can we expect you to have any kind of, I guess, FDA interactions in the near term so we kind of have a better understanding of how they think about these results? 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. Thanks. Yeah. 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 it to the FDA, I do believe we probably have some impact on the future development. To be direct, the FDA has never really raised major issues about the risk of abuse. These data were required for the NDA, not for running three phase III trial that they are ongoing now. I would say that definitely they will help. We have a former FDA high officers on the call, maybe Frank or Vocci would want to comment on this. The question is what this data will mean for the future and dealing with the FDA on the development. I would 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. I think I would predict that when you look at the totality of the data, including people in 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. 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 loosing a drug on the American public that is going to turn out to have an abuse problem. Right. This is Henningfield. Let me just add, I mentioned before, scheduling is based on the totality of all of the evidence. At the College on Problems of Drug Dependence meeting, we presented two studies in animals. One looked at the reinforcing or rewarding effects in the intravenous self-administration model. That found no evidence of reinforcing effects in rats. The other looked at physical dependence withdrawal in a rat model. Again, 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. All of that will be considered. Right now, this is a pretty favorable-looking profile compared to a conventional opioid. 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. Basically you're saying it's all about the sum of totality of evidence, which everything's pointing in the right direction. As I think about eventual scheduling, I mean, I understand FDA, DEA, they weigh in this eight-factor analysis. I guess, how should we think about the importance of this abuse liability study as well as the ketamine study relative to these other seven factors? Just to be clear, I'd assume that the other seven factors just stack up very favorably in your view. You're confident the other seven factors are great, too. Thanks. Yeah. Jack or Frank? 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. I think that's very good. 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 in a 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. 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. 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. From a practical standpoint, there's really two schedules. It's one and two versus III, IV, and V. Drugs in Schedule I and II are very strictly controlled and regulated. Drugs in III, IV, and V are much less strictly regulated and controlled. I think this study clearly shows, without any argument, that REL-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'll be in the lower schedules. One of the lower schedules, which are significantly less restrictive than Schedule II. I think, the real takeaway from this is that it's not a conventional opiate. There's no way that it would ever end up in Schedule II. It'll most likely be in one of the lower schedules. Fantastic. Really quickly, did you guys happen to capture AEs of special interest, like euphoria and relaxation or even dissociation and hallucination? Can we expect the AE data down the road? Thanks. I hope there's somebody, maybe Paolo Manfredi or Marco Pappagallo, that have seen all the data. We are not aware of any particular AEs. We would know if there was any issue related with that. The study was not designed to detect these kinds of things. If there was something that was spiking, clearly, we would've been told. I'm not aware of anything. Paolo or Marco? Yes. Confirmed. Agree. That's Marco. All right. Very good. See you. This is Marco Pappagallo. Yes. There were none. To answer the follow-up, we are going to be presenting this data at conferences, and we will have the full picture at that time. No concerns about adverse events of special interest. Great to hear. All right. Congrats again. Thank you. Our next question comes from the line of Jay Olson with Oppenheimer. Please proceed with your questions. 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. It sounds like there's a consensus around Schedule IV or V based on these data. 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 REL-1017. I had a second question, if I could. Thank you, Jay. 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. The expectation was, four or five is a fair scenario, not because the drug should deserve and be controlled, but because of the whole process of descheduling a drug. Straight answer is yes. They are perfectly in line with our expectation and with what the previous data they have shown. Chuck, you want to comment on that from the old data? Certainly, I can comment briefly on the old data. There were two early studies done at the Addiction Research Center. One was done around 1946, published in 1948. That was just after methadone was brought to the United States after World War II. The other was published in 1962. I 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 was 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 then somehow they got to very high doses, up as far as 1,000 mg. Even at those doses, there was a lot of disliking, a lot of negative effects. Although it did have some indication of opiate-like activity, patients, and this was very small numbers, they did something like only five patients in the critical study that was reported in 1962. Still, the conclusion was very low abuse liability. 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 1940s, certainly, and even in the 1950s and 1960s. Methodology has developed quite a bit and much more sophisticated now, including statistical analysis, including the way the questions were worded, the kinds of scales that were used. 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. 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 mg, and found no evidence of any opioid-like effects at all. The overall conclusions are very consistent with the data we see now. Great. That's super helpful. Thank you for that. 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 Jack Henningfield. I published with Roland Griffiths and colleagues at Johns Hopkins an eight-factor analysis. This is premature. The NDA hasn't been filed. A lot of data are to be gathered yet. 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. Again, that's premature, and I think the important point that Frank Sapienza made earlier is you can think of really two general categories of scheduling. Schedule II and above, or Schedule II and Schedule I, and everything below. I just don't see anything about psilocybin that makes it look like a Schedule II drug. Where it will end up, we'll have to wait. This is Frank Sapienza. I'm not going to 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. 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 shouldn't go into schedules lower than Schedule II. Super helpful. Thank you very much. Yeah. The next question comes from the line of. Operator. I'm sorry, please go ahead. No, go ahead. I'm sorry. Our next question is from the line of Marc Goodman with Leerink Partners. Yeah. Good morning. I guess first of all, there were 50 patients that went into the study, and 44 were evaluated. Just can you talk about the six that were not? In these type studies, is that a usual number of patients that are not evaluated, and why were they not evaluated? Secondly, you kind of breezed through it by saying all the secondary endpoints were consistent. Is there any more color you can give us about some of the secondary endpoints? I mean, to take the drug again, were all of these basically exactly the same with respect to the primary endpoint as far as the shape I'll comment on the size, and maybe Sergio can comment more on specifics of other endpoints. For a FDA registration trial, this is pretty typical. A little larger than some. There are few that are larger than this. For an academic study, those are usually 10-15. Dr. Gorodetzky mentioned the Addiction Research Center, where I also was. Most of our studies were around 10 people. Right. Jack, maybe you saw the data. You may want to comment on the secondary endpoints that are in line with the primary. Yes. 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. These, I don't have the actual numbers in front of me, but the patterns were very similar to liking. That's important because every once in a while, we see a drug in which the acute liking is relatively low, but the total global is high, and people say, "I would take it again," and rate it highly. We didn't see that here. With respect to the numbers, my question wasn't, was 44 a big number of patients for a study? It was more of, we started with 50, and we ended with 44. What happened to the other six? Is that typical in these type studies for that percentage to kind of not be evaluated? Yeah. Marc, I can give you the top-down, Paolo Manfredi or Marco Pappagallo can give you some more detail. This is special patient population. I do believe that three or four, they just didn't show up. They had to come in 5x, and if somebody does not show up for 1x, is automatically excluded from the trial. There were two or three that were not evaluable for the results. These are people that don't recognize oxycodone, they had the score of oxycodone, like 50 or 70 for placebo or it was purely technical. There was a very rigid criteria for inclusion exclusion after the data were unblinded. There were, I believe, two or three patients. That result didn't make any sense. These are the six patient missing. No side effect, nothing that would be worrisome. It's pretty normal for these kind of studies. Yeah. That's pretty typical. Yeah, it's a pretty typical number. It's rare that out of 50 subjects, they all get through all conditions. Thanks. Thank you. The next question comes from the line of Eddie Hickman with Guggenheim Securities. Please proceed with your questions. Yeah. Hey, guys, this is Eddie. Thanks for taking my question. 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? Given these data, can you just sort of reset your expectations for the ketamine study on timing and then sort of what you're looking for? For the expert, sort of 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. 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. Yeah, the first part was the implication of the difference at the maximum tolerated dose with placebo, what the implication can be. Well, the main thing is, to my eye, it's a very small increase. It's a relatively shallow increase. We have seen drugs where they were also fairly shallow dose response curves. I've published studies with some of these drugs. Then at the supratherapeutic dose, there's a robust bump that comes close or overlaps with oxycodone. We didn't see that. Yeah. The high dose 150, if I recall correctly, the median was 58. That basically tells you that 22 people out of 44 were between 50 and 58, and that the other 22 were above 58. When you average them all together, they're at 64.9. There is a range of people, and there is probably somewhere around one out of every three people recognized this as something that they liked. It was only that. When you look at the mean score and the medians, they don't differentiate from placebo. I think it's very reassuring that you're at a top dose there, 6x the therapeutic dose, and some people are barely getting some perceptible effect. Even that, this is Chuck Gorodetzky, even at the 150 mg dose, it's still pretty much similar to placebo. It would not be at T less than 0.001, but it'd be T less than 0.1. There's really not a big bump there. Right. If you look at the median score for oxycodone, the median score for oxycodone was 89, I believe. It's 58 versus 89. You see, when you look at the medians, people are far more likely to recognize oxycodone as an opioid and score it very highly. Got it. Thanks. On the ketamine study, sort of what are you expecting? For the experts, what would you need to see in that study that would imply a Schedule III? My expectation would 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 were ketamine experienced found this to be nearly as pleasurable as ketamine. 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. Yeah. I think it might also be important, this is Chuck Gorodezky. 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. If we can help in the 44 patients evaluated in this study, we have not seen, there is no report of hallucinogenic effect. That looks some way, an anticipation of what we should see on the ketamine study. It's confirmed by the phase I and the phase II. Even at the maximum tolerated dose, there is no psychedelic or not even close to psychedelic effect. Great. Thank you so much. Thank you. At this time, I'll turn the floor back to management for any further remarks. Thank you, operator. 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. Those individuals suffering from depression are really in great need in something new, safe, and rapidly effective treatment. With these compelling results, it has increased 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 as a new, novel, safe, and fast-acting treatment for depression. We are excited about the catalyst important that lie ahead of us, mainly the phase III and so on, and the ketamine study. We'll keep you updated on clinical readouts and activity through the remainder of 2021. Thank you all for joining us, and I wish everyone to enjoy the rest of the day. Thank you very much. Thank you, our advisor, of course. Thank you, everyone. This will conclude today's conference. You may disconnect your lines at this time. Thank you for your participation.