Greetings. Welcome to the Ramada Therapeutics Corporate Update Call. At this time, all participants are
in a listen only mode.
A brief question and answer session will follow the formal presentation. 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, Ramada's management team will be making forward looking statements. All 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 RealMod's press release issued today and the company's SEC filings, including the annual report on Form 10 ks 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. Ramada 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 Taverza, the Co Founder and CEO of Remada, and 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 REL10-ten versus Oxycodone. On Slide 3, you will see a brief agenda for today's call. As an opening remark, we are fully aware that there is there was an investor concern about the potential for abuse of rel1017 due to the relation with the parent well known parent drugs. There is considerable data already published indicated that RLM1017 does not carry abuse including very clear statement from the 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 work closely with experts in this area that helped us and we 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 data today. Jack is from P and A Associates.
He's a world renewed 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 of the National Institute of Drug Abuse, the NIDA, and is an advisor to Ramada. Following the presentation, we will open up the calls for your questions, and we'll be joined by 3 very experienced gentlemen, doctors in the field of abuse, Doctor. Charles Gorodetsky, that is the former Director of the National Institute of Drug Abuse, the NIDA, and at the Resource Center in Lexington, Kentucky Doctor. Frank Bocci is former Chief of the Abuse Staff at the FDA and former Director of NIDA Medication Development Program and Frank Sapienta, former Chief Drug and Chemical Evaluation Section at 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 covered high position at this agency. With no further delay, I will now turn the call over to Jack, and he will review the study design and the results. Jack? 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 Gorodetsky and Sapienza Invacci. 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 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 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 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 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 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. 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 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 milligrams of oxycodone was the positive control drug and that is the most common drug recommended by FDA for such studies. 3 doses of REN017 were tested. The 25 milligram daily therapeutic dose, then a 3 times higher dose, which is 75 milligrams. And then somewhat unusually, quite frankly, is a 150 milligram super therapeutic dose. That was 6 times 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 five treatment phases. The primary endpoint 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 endpoint drug liking at this moment of AR1017 versus oxycodone. Now, eMAX or the highest drug liking is shown across the treatment arms. Note that the mean and median for EMAC across all treatment groups is statistically and the statistical significance and all treatment arms including placebo and REO-ten seventeen doses are highly significantly different from oxycodone.
And that was true at all of these 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 milligram AR1017 as compared to 40 milligrams of oxycodone. Thus, 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 6 times therapeutic dose.
Let's look at the next slide. And this compares RAL1017 to placebo statistically. What you see is the median values for liking scores for RAL1017 at 25 milligrams and 75 milligrams are the same as placebo. By the way, in most of these studies, FDA recommends a 2 to 3 times higher dose than therapeutic. So at the 3 times 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 milligrams of AR1017 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 Take the Drug Again and they showed similar patterns and these further strengthen 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 of more. First, all, REO-ten seventeen doses showed highly REO-ten seventeen doses of were not significantly different from placebo at the therapeutic range and the 3 times therapeutic.
The key secondary endpoints are consistent with the findings are consistent with DEA's current statement on Methadone. And as the Drug Enforcement Administration states, the de isomer lacks significant respiratory depressant 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 non scheduled drugs as well as Schedule IV 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 AR1017 does not produce subjective effects that are similar to a conventional opioid. Now we've got doctors Gorodetsky, Sapienza and Voci 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 differentiate rel1017 or any potential perceived association with opioid effect as just stated. And this data will be part of the planned NDA new drug application submission for rel=ten seventeen 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?
And our first question is coming from the line of Andrea Tan with Goldman Sachs.
Thanks for taking the question. Congratulations on the data today. Sergio, maybe a question for you here. Given the profile of 10/17 that you observed in this study, where those mean emacs scores were in the 50s, 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 BASS 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 our experts on the 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 1, 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, 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 the way you expected. And the second part, I will let some of the experts to comment.
This is Frank Bacci. I would say that the 25 milligram and 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, Doctor. Boccchi or Doctor. 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 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 and 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 de control. 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 10/17 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 de control it. But that's why one of the main reasons why I think we think that although this would not be a Schedule 2, it would probably end up being scheduled somewhere in one of the lower schedules.
This is Chuck Oredeski. 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 3 times therapeutic maintenance dose, which is the initial dose and even the very small increase that we see when we go to 6 times the maintenance dose. So I think this very much looks like it should be somewhere in the lower schedules like a 4 or 5.
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 the 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 5 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 when it after it is marketed.
This is Frank Botti. I agree. I think it would be a 2 stage process, probably 45 and then later with post marketing data and the international control issue resolved, it could go on scheduled.
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 and 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. And you also tested the 6x dose, the 100 50 milligram dose. What does that do for you in terms of labeling discussions with the FDA and scheduling discussions with the DEA?
Only asking because you our understanding is that you required to test up to 3 times a dose, but you went ahead and tested the 6 times 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 3 times higher.
The thing is this 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 3 times. I think the fact that they went to 6 times makes the my confidence in the outcome stronger because it really pushed it. Any others want to comment on other aspects of that?
This is Chuck Ordetsky again. I agree, Jack. I think that 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.
Right. 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, we'd love to hear that. Thank you.
Chuck, Frank, Frank, do you have any insight 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 for you folks.
No, I don't. Could you repeat the question? This is Frank Saffienza. I'm sorry, I missed it.
Yes, yes, yes. So as Epidiolex move along the DEA scheduling and eventually was not scheduled at all, was there concurrent uptick in prescriber adoption
of the tablet? Oh,
cool. Yes. 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 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.
Yes, John, 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 pattern for Schedule 4, 5 and non scheduled, if you look at the market around the DVB and not a big difference. So there is no difference at all.
Got it. And 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. 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 esomethuran or are you looking to develop this as a complementary to esomethuran?
Just curious what your strategy is there. Thank
you. Yes. Thank you, John. 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, while the mechanistically, psilocybin is a 5OH2A and agonist, and it fit with the neuroplastic concept and neuroplasticity that we are focusing on and mesmethadine, but then 17 works with a similar or same goal with a different mechanism to this NMDA blocker. But the strategy there is complementary in term of science. But for Cylu Fibia, 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. Got it. Thank you.
This is Jack Henningfield. I'm working on psilocybin and other substances as well. And remember, we've got more than 17,000,000 people with major depression in the United States, about 300,000,000 worldwide. And what's really important about AR1017 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 whole 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 and congrats on the nice data readout. So I have two 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 kind of 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. Thanks.
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 will 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, but not for running like 3 Phase III trials that they are ongoing now. So but I would say that definitely they will help.
But we have a former FDA high officers on the call. So maybe Frank or Uchi would want to comment on this? So the question is what this data will mean for the future and dealing with the FDA on the development.
Well, I mean, 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 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. 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 is going to turn out to have an abuse problem.
Right.
This is Henningfield. Let me just add, I mentioned 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 rats.
And the other looked at physical dependence withdrawal in a rat model. Now again, and that's did not see evidence of withdrawal compared to morphine. Human data are the most important. There are the Phase 3 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's 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 the ketamine study relative to these other seven factors? And 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.
Yes. 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. So I think that's very good. So the fact that the 6 fold dose gave a slight indication that it is still right at the height of the placebo response rate, that is a very 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. 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 Saffiganza. So in the world of scheduling, do you have drugs that are in Schedule 12 and then you have drugs that are in Schedule 3, 45. And from a practical standpoint, there's really 2 schedules. It's 12 versus 3, 4 and 5. Drugs in Schedule 12 are very strictly controlled and regulated.
And drugs in 3, 45 were much less strictly regulated and controlled. And I think this study clearly shows without any argument that 10/17 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 less restrictive than Schedule 2. So 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 and 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.
Yes. I hope that somebody that maybe Doctor. Monfredi or Doctor. Galvo, 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 there was something that was spiking clearly, we would have been told. But I'm not aware of anything, Paolo or Marco?
Yes, confirmed. Agreed.
Yes, that's my role.
This is Doctor. Barbagallo. Yes, there were none.
And to answer the follow-up, we are going to be presenting these data at conferences and we will have the full picture at that time that no concerns about adverse events of special interest.
Okay. 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. And it sounds like there's a consensus around Schedule 4 or 5 based on these data. So I was wondering if Sergio if you could please comment on how Schedule 4 or 5 lines up with RAYMONDA's expectations and how that would impact the commercial opportunity for 10/17? And then I had a second question, if I could.
Yes. Thank you, Jay. Yes, but look, we are discussing in the past, based on the evidence of the published data with Doctor. Gorovetsky was involved in the early stage of his career, so he can comment on this. But the expectation was 4, 5 is a fair scenario, not because the drug should serve and be controlled, but because of the old process of the scheduling 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, 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, 1 in 19 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. 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, 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 this is 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 60s methodology has developed quite a bit much more sophisticated now, including statistical analysis, including the way the questions were worded, 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 19 50s, 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 opioid like effects at all. And the overall conclusions are very consistent with what the data we see now.
Great. That's super helpful. Thank you for that. 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?
Well, 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 2 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 that Frank Sapienza made earlier is you can think of really 2 general categories of scheduling, 2 and above and 2 and 1 and everything below. And if that 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.
Yes. This is Frank Sapienza. I'm not going to comment on necessarily where psilocybin should go, but colucinogens in general were put in Schedule 1 primarily because they had no currently accepted medical use, which was a criteria for drugs in Schedules 2, 3, 4 or 5. So because they had an abuse potential, they automatically went into Schedule 1. 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 2.
Okay, super helpful. Thank you very much.
The next question comes from the line of I'm sorry, please go ahead.
No, go ahead. I was sorry.
Our next question
is from the line of Marc Goodman with SVB Leerink.
Yes, good morning. 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 in these HAP 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 second 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 endpoint as far as
the
I'll comment on the size and maybe Sergio can comment more on specifics of other endpoints. 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 Doctor.
Gorodetsky mentioned the Addiction Research Center where I also was. Most of our studies were around 10 people.
Right. And the Jack, maybe you saw the data, you may want to comment on the secondary endpoints 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 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. And so what happened to the other 6? And is that typically a DTaP study for that percentage to kind of not be evaluated?
Yes. Mark, I can give you the top down and then Doctor. Monfredo or Papagalo can give you some more detail. But this is national 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 it's automatically excluded from the trial. And there were 2 or 3 that did not 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 that result that didn't make any sense. These are the 6 patients, no side effect, nothing that would be worrisome.
It's a pretty typical number. It's rare that out of 50 subjects, they all get through all conditions.
Thanks.
Thank you. Next question comes from the line of Eddie Hickman with Guggenheim Securities. Please proceed with your questions.
Yes. Hey, guys. This is Eddie on for Yatin. 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?
And then 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? 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.
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
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've published studies with some of these drugs. And then at the super therapeutic dose, there's 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 5058 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. I think it's very reassuring that you're at a top dose there 6 times the therapeutic dose and people are some people are barely getting some perceptible effect.
And even that this is Chuck, this is Chuck Oresteschi, 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 P less than 0.1. There's really not a big bump there.
Right. 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 high.
Got it. Thanks. And then on the Ketamine study, sort of how are you what are you expecting? And then like for the experts, 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 rel1017 and that you would have to have something that exceeded that, that would essentially exceed my expectations that individuals who had who were 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 3.
I think it might also be important. This is Chuck Korodetsky. I think it might also be important when we look at the secondary measures, including, what drug they identify it as, to identify it as a hallucinogen, to identify it as a sedative, to 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 was no report of hallucinogenic effect. So that looks some way in anticipation of what we should see on the ketamine study. And is confirmed by the Phase I and the Phase II. Even at the maximum tolerated dose, there is no psychedelic or 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. 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 and something new, safe and rapidly effective treatment.
And with these compelling results, I mean, I increased our confidence in the ongoing rel=ten seventeen late stage development program. Based on the collective data that we have generated to date, rel=ten-seventeen 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. 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 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.