Ladies and gentlemen, thank you for standing by, and welcome to the Relmada Therapeutics, Inc. First Quarter 2022 Earnings Call. During the presentation, all participants will be in a listening mode. Afterwards, we will conduct a question-and-answer session. At that time, if you have a question, please press the one followed by the four on your telephone. If at any time during the conference you need to reach an operator, please press star zero. As a reminder, this conference is being recorded Thursday, May 5th, 2022 . I would now like to turn the call over to Tim McCarthy, LifeSci Advisors. Please go ahead.
Thank you, Ingrid, and thank you all for joining us this afternoon. With me on today's call are Chief Executive Officer, Sergio Traversa, and Chief Financial Officer, Maged Shenouda. This afternoon, Relmada issued a news release providing a business update announcing financial results for the three months ended March 31st, 2022, and filed its quarterly report on Form 10-Q with the SEC. Please note that certain information discussed on the call today is covered under the safe harbor provisions 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 in the annual report on Form 10-K for the year ended December 30th, 2021, and subsequent filings. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, May 5th, 2022. 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 Sergio. Sergio?
Thank you, Tim, as always. Good afternoon to everyone, and I'm pleased to welcome you to the Relmada First Quarter 2022 Conference Call. During today's call, I will review our recently achieved milestones and the anticipated timelines associated with the multiple expected clinical trial readouts for REL-1017. That is our lead product candidate that we're currently developing as an adjunctive and monotherapy treatment for patients with major depressive disorder, or MDD. Following my comments, Maged Shenouda, our Chief Financial Officer, will review our financial results and balance sheet, and then we will take your questions. As many of you know, we expect 2022 to be a catalyst switch year for Relmada. We intend to generate REL-1017 clinical data readouts beginning mid-year for the ongoing RELIANCE phase III trial.
Specifically, we anticipated completing the enrollment of RELIANCE III, the ongoing monotherapy registrational phase III trial, followed by top-line data readout by mid-2022, and followed by top-line results from RELIANCE I and RELIANCE II respectively. These anticipated timelines remain unchanged from prior guidance. As a reminder, RELIANCE I and RELIANCE II are two ongoing phase III sister two-arm placebo-controlled pivotal studies evaluating REL-1017 25 milligrams as a potential adjunctive treatment for MDD. RELIANCE III is the ongoing phase III two-arm placebo-controlled registrational study evaluating REL-1017 25 milligrams as a potential monotherapy treatment for MDD. All participants in the RELIANCE trials take a loading dose on day one of 75 milligrams. That is three tablets of REL-1017. We made significant progress in advancing our development program. To this end, in February 2022, we reported top-line data from our second HAP, or Human Abuse Potential Study, which compared REL-1017 versus intravenous ketamine.
Our first HAP study comparing REL-1017 versus oxycodone was successfully completed in July 2021. Most importantly, the findings from these two HAP studies were consistent and confirmed the 2019 DEA statement on esmethadone that states that the D isomer lacks significant respiratory depression action and addiction liability. We believe that oxycodone comparative data significantly de-risk the Schedule II potential for REL-1017, and then the ketamine comparison data significantly de-risk the drug candidate Schedule III potential. As we have said previously, we believe that the data generated to date from our ongoing development program indicates that REL-1017 could be initially proposed as a Schedule V drug, with potentially to eventually a non-scheduled drug following one or two years of marketing experience. Moving on to the current status of the phase III program.
We continue to anticipate the completion of enrollment in RELIANCE III, the ongoing monotherapy registrational phase III trial, followed by the top-line data readout by midyear. RELIANCE III aims to randomize up to 364 patients who have been diagnosed with depression and are not currently taking a standard antidepressant. The study includes two arms, placebo and 25 milligrams of REL-1017. Patients may have tried no more than one standard antidepressant in their current major depressive episode to be eligible for the study and have to be off treatment for at least the 30 previous days. Conducting RELIANCE III as a phase III study could meaningfully reduce the time for a potential approval of REL-1017 as an MDD monotherapy.
Let me now provide an update on the ongoing RELIANCE I and RELIANCE II studies, each of which is designed to include up to 364 participants per study across 55 sites per study. RELIANCE I and RELIANCE II are designed to evaluate REL-1017 as an adjunctive treatment for MDD, and both include two arms, placebo and 25 milligrams of REL-1017. Both arms are studying the use of REL-1017 in addition to a standard antidepressant for participants who have had inadequate response to at least one and up to three standard antidepressant therapies. The primary endpoint is the change in MADRS score of the drug versus placebo at day 28. Key secondary endpoints include the change in MADRS score on day seven and change in the Clinical Global Impression Severity Scale, the CGIS score, at day 28.
Day 28 was chosen as a primary endpoint in agreement with the FDA, with an understanding that depression is a chronic disease and that day 28 will support REL-1017 as a chronic treatment. Both RELIANCE I and RELIANCE II are progressing as planned, and we continue to expect the availability of top-line data in the second half of this year. The RELIANCE development program also includes RELIANCE-OLS, the long-term open-label safety study that is enrolling both rollover participants from all three pivotal studies as well as the de novo participants. RELIANCE-OLS is ongoing and continues to enroll participants as planned. Data from this long-term open-label safety study will be part of the planned NDA filing package. As REL-1017 development program advances, we continue to expand our senior team.
To this end, I'm very pleased to report today that we appointed Gino Santini as corporate development strategic advisor. He's a veteran global biopharmaceutical industry executive with strong P&L experience that demonstrated value creation skills. Gino has a successful track record in both operational and strategic growth, worked in three different continents and in various areas of the pharmaceutical value chain. He is a former member of the executive team, Eli Lilly, most recently as President of U.S. Operations and SVP of Corporate Strategy and Business Development. He has a broad global network in the pharmaceutical biotech, VC, private equity, and investment banking communities. He retired from Lilly in December 2010 after a career of 28 years. Gino currently serves on boards of multiple public and private biopharmaceutical companies.
I also would like to highlight that REL-1017 data were presented last month in two poster presentations and one oral presentation at the Ketamine & Related Compounds International Hybrid Conference 2022. In addition, REL-1017 preclinical Olney's lesion data were recently published in the peer-reviewed journal, Frontiers in Pharmacology. This compelling data confirmed that REL-1017 does not produce Olney's lesions, unlike what has been seen in other NMDA antagonists. In REL-1017 treated rats, Olney's lesions, which usually appear one day after treatment with MK-801, that is another NMDA channel blocker that was used as a positive control in the study, were not observed. These results further contribute to the safety profile of REL-1017.
Finally, I would like to highlight that May is Mental Health Awareness Month, which serves as a reminder for us of why we are so passionate about advancing our core mission at Relmada. To mark the occasion and increase visibility around mental health, we are participating in a number of initiatives this month, including sponsoring the 33rd Annual Lifesavers Gala 2022 that is hosted by the American Foundation for Suicide Prevention. Several members of our team will be participating in local walks sponsored by the National Alliance on Mental Illness. With that, I will now turn the call over to Maged for a review of the financials. Maged, the stage is all yours.
Thank you, Sergio. Today, we issued a press release announcing our business and financial results for the three months ended March 31, 2022, which I will now review. For the first quarter ended March 31, 2022, total research and development expense was approximately $25 million as compared to $14 million for the comparable period of 2021. The increase was primarily related to an increase in costs associated with the execution of a broader clinical program for REL-1017. Non-cash R&D expense for the first quarter 2022 amounted to $1.3 million. Total general and administrative expense for the first quarter ended March 31, 2022 was approximately $13.3 million, as compared to $8.4 million for the comparable period of 2021. An increase of approximately $4.9 million. The increase was primarily due to the increase in stock-based compensation.
This non-cash charge totaled $10.7 million in the most recently completed first quarter. For the first quarter ended March 31, 2022, we recorded a net loss of $39.7 million, or $1.40 per basic and diluted share, compared to a net loss of $22.2 million or $1.34 per basic and diluted share in the comparable period of 2021. As of March 31, 2022, we had cash equivalents and short-term investments of $220.6 million compared to cash equivalents, and short-term investments of approximately $211.9 million at December 31, 2021. I will now ask the operator to please open the call for questions. Operator?
Certainly. Thank you. If you would like to register a question, please press the one followed by the four on your telephone. You'll hear a three-tone prompt to acknowledge your request. If your question has been answered and you would like to withdraw your registration, please press the one followed by the three. One moment please for the first question. Our first question comes from the line of Andrew Tsai with Jefferies. Please proceed with your question.
Thanks for taking my questions. The first question is actually on the kinetics of the phase III monotherapy data coming out. Well, it also applies to the adjunct study. I guess my question is, you know, how do you foresee the curves to look like, you know, for esketamine in particular as well as placebo, from day seven to day 28? You know, should we be expecting no kind of rebound in terms of the efficacy or is some rebound actually okay in your view? Thanks.
Well, thanks, Andrew. Sergio, let me take this one. Well, of course, we don't have data, especially monotherapy. We don't have any data, not short-term, not long-term, but we have very strong adjunctive treatment data, and we have experience, so we have data from other compound that also work on the NMDA channel. Just based on what we have seen from phase II and, you know, based on what is the experience from other similar compounds, we don't expect any loss of efficacy over time. Actually, based on the mechanisms and if we do believe, and we do believe the neuroplastic effect, then, you know, longer term the efficacy of the drug should just improve. We don't expect any loss of efficacy after day seven. We expect to be stable and hopefully better than day seven.
Right. Okay. Very good. Secondly, it's more of a high-level question, maybe more open-ended. It's just, you know, I guess, conceptually, you know, what do you guys think you've done for these phase III studies to maximize their product success? You know, what are you doing differently than the other companies with depression programs? Anything in the inclusion criteria or COVID protocols, you know, maybe something about the placebo response or even the drug effect? Any color would be great.
Well, thanks, Andrew. This one, it will take some time to go more in detail of what we have done. You know, top down, we have done everything it is possible to think about it to make the effect of the drug to confirm what we have seen in phase II. Without making too many, like, strong statements without the data, based on phase II, we do believe the drug is safe, is well tolerated, but also that the drug works, you know, has a very strong efficacy. We don't see any reason why the drug should not confirm the same effect in the phase III program.
What is the, you know, potential, right, the potential risk of what everybody is afraid in every trial, but especially in depression trials, the placebo effect. What we have been focusing on is everything is possible to do to like control the placebo effect. That means the site selection, trying to get sites with experience in depression clinical studies, rater selection. The rater is actually trained by a company that is called CTNI. Hopefully, I'm not making any publicity for anybody. But it is the company that administer the SAFER interview to the patient. At the same time, they train the raters.
The site, the raters, you know, looking at the profile of the patients that the SAFER interview that should support, like a patient selection that would exclude patients that are not affected by depression and to, like, support or be sure that the patient, the compliance that the patient takes the drug. That's, you know, there is a little video that is uploaded every day showing that the patient is taking the tablet. Reading a statement before every MADRS interview that the patient has to read that states that he has 50% chances to be on placebo, a pattern that reduces the placebo effect and so on, right. There is no magic.
There is no magic bullet or magic strategy that can guarantee you the results. We do believe that all we have done so far to support quality of the patients, compliance and should support, right, the.
Yeah.
A good control of the placebo effect.
Very good.
I hope I don't answer, but I hope I answer you. I want to answer you. Maybe in more detail.
Right. I think it's important. Very last question is, you know, in addition to kind of monitoring for, you know, discontinuation rates and the rollover rates which you've disclosed before on a blinded basis, let's be clear, are you looking at anything else on a blinded basis? I don't know, total MADRS changes. Are you able also to confirm the DMC committee is still seeing no signs of opiate or dissociative effects? Thanks.
Yes. I answer first the second question. It is easier. Yes, the DMC has not. From the last meeting of the DMC and their statement to continue as planned, we have not heard anything different about any severe side effect or any change in the program. Yes, the answer is yes. If there were anything that would suggest to change something in the study, that would also mean if there is withdrawal symptoms of anything that is unusual that would pose any risk for the patients, then we would have known. We assume that, from the review, there was no sign of any withdrawal effects. Remind me the first question that I lost a little bit there.
Mm-hmm.
Yeah, I was focused on the second one.
If you're seeing anything, right. If you're seeing anything else on a blinded basis, basically.
I'm not trying to avoid it. No, no. Look, the blinded data, they are extremely useful for safety. Then if there is no sign of any severe side effects, you assume that we assume the placebo does not give severe side effects. You see nothing. So it's fair assumption that the drug is safe and well tolerated. On the efficacy, well, it would be highly risky to look at blinded data and to make any statement. Until you know what the placebo does, it's impossible to draw any conclusion. Probably we would see if there is zero effect, right? If everything would be a zero, right? You assume that nothing is working, so the drug would not work. But yeah, that's all you can tell.
Mm-hmm.
We don't believe, right, we'll see a zero effect, but that's not an indication of any final results. We have to be a little patient here.
Understood. Very good. Fingers crossed, and thank you for taking my questions.
A pleasure, Andrew Tsai, as always.
Our next question comes from the line of Andrea Tan with Goldman Sachs. Please proceed with your question.
Hey, everyone. Thanks for taking my question. Sergio, maybe just two for you. Just curious if you could speak a little bit more on your estimates of the size of the monotherapy opportunity. Do you envision positive data from RELIANCE III could prompt inclusion on REL-1017's label, or do you think you would need to run an additional study and submit a supplementary filing thereafter?
Thanks, Andrea, and good afternoon to you as well. Thanks. Thanks for the question. In moving forward, the next calls, we will be probably a little more precise on the size of the market and with Gino on board, one of the role he'll help would be to regive us guidance and help us in determining what the size of the different opportunities are. Now, monotherapy, it's very much related with the clinical data. That's where there will be the big difference, right? Because competition in adjunctive treatment, there is no antidepressant approved. The only three drugs and they're all antipsychotics.
That makes the task not easier, but you know, definitely a little bit more favorable because you know, if REL-1017 makes it to the market as an adjunctive treatment, that would be the only antidepressant available. There is going to be more price power and less direct competition. Monotherapy, the competition is generic 26-27 drug with one exception that I believe is Pristiq, is the only branded antidepressant left. Price will be critical, price competition. Price competition can only be overturned by one factor, is clinical data.
If the data in phase III monotherapy will be even everywhere close to the phase II, then we do believe, I do believe we have a good chance because you go against drugs that have a, an effect size of about 0.3 and they work in about 30%-40% of the patients, take a month at least to show any efficacy. They are not exempt from side effects. If the data, what we hope and we expect to be, that you have a drug that you take one tablet in the morning and it works after a few days, it is effective chronically and it's effective in whatever we've seen in phase II. In non-responder to traditional antidepressant, response rate was very close to 60%. Six out of 10 patients responded.
That's gonna be very difficult for payers to recommend as a frontline traditional antidepressant. The clinical data will really drive the size of the market. Price will be a very important factor. We'll be more closely with the payers, you know, in the next few months, and we will have a better understanding of what they want to see to put REL-1017 as a frontline therapy, even as a reimbursement. I hope I answered your question.
Perfect, Sergio. Just and then on the second part, just if you, I guess maybe based off of initial conversations with the FDA, if you have an idea whether you would need to run an additional study there, or if this could be, you know, somehow grouped into an existing label for the adjunctive use case.
Yeah. It is. Well, to be direct, we did not address with the FDA this aspect. The FDA was in line with running a phase III instead of a phase II, so that could be read as a positive indicator. Again, the data will drive. If the data will be compelling, we don't see any reason why we should have to run a second monotherapy trial. If the two adjunctive trials will be positive, right? We go to the FDA with three trials with compelling data, positive, plus the long-term safety that doesn't show any issue. We kind of seen that the potential for or the risk for abuse doesn't seem to be there at all.
That would make a very powerful package for the FDA. Yes, if everything goes the way we hope and we think that the phase III trial will be successful and we won't see any safety and risk, then we assume that we won't have to run a second phase III monotherapy trial. We don't think we add any more information on what is already available.
Great. Thanks, Sergio.
Thanks, Andrea.
Ladies and gentlemen, as a reminder to register for question, please press the one followed by the four on your telephone keypad. Our next question comes from the line of Yatin Suneja with Guggenheim Securities. Please proceed with the question.
Hey, guys. Thank you for taking my question. I have a couple very quick ones. First one is, can you just talk about how you might be modeling the placebo rate, given that this is now outpatient versus the inpatient that you conducted, and what your expectations are over the four-week timeframe? Because in your study so far, we've just seen two-week data. That's the first question.
Sure. Let me answer the first one and then give you the line, and you can ask the second one. The placebo effect, right? That is a critical topic that, you know, we have really thought about in from every different angle. Let me give you the numbers that we thought about putting into the statistical model. In-clinic inpatient treatment, they tend to have a higher placebo effect. There is an advantage in running an outpatient trial the way we are doing with the RELIANCE program. On the other side, our phase II was seven days treatment. Placebo was taken for seven days. Placebo tend to have a gradual increase over time for a variety of reasons.
We do believe that these two factors, they balance themselves, right? If you look at the placebo effect in phase II, was, I believe, if I remember correctly, eight points after six to seven days. That's a pretty high placebo response. We have seen numbers in other trials that go from four, five, six. They tend to be lower in an outpatient setting. The inpatient played a role and the placebo effect was higher than in outpatient. In the assumption that now we have a trial with four weeks, I think remember in the statistical plan, we assume that the placebo will be 12 points.
If the placebo delta from baseline to day 28 would be 12 points then, and with the assumption that, REL-1017 will behave and perform the way it has done in phase II, then the trial will be highly successful. Anything below 12 points delta from baseline for placebo to day 28, would be like, I don't know what kind of term I should use, but would be a very successful trial. If the placebo performs from baseline above 12 points, it depends. If it's 13, 14, it's still manageable. We do believe, the trial will still be successful. If it is above 15, that, you know, I don't see much. I haven't seen many of these. I haven't seen these numbers. If placebo is above 15, then we have a problem.
You can assume that 12-point delta from baseline to day 28 for placebo is the key number to look at. If it is below that, the trial will be highly successful.
Got it. Very good.
If it is slightly above, we'll still be successful.
Got it. Very good. Thank you very much. Can you confirm if patient in all three phase III studies are receiving a loading dose, and what is that dose? Is it the 75 milligram dose and then they go into 25 dose? Can you maybe just talk a little bit about, specifically about the pharmacology that requires a loading dose if you are using?
Sure. Happy to do that. Yes. The answer is yes. All three studies are taking the loading dose. I do believe that also for new patients, also the long-term safety study starts with a loading dose. That it is 75 milligrams is three tablets. I'm happy to share that even taking three tablets the first day, we have seen nothing in terms of serious, severe or side effects. That is confirmed by the discontinuation or dropout rate that is well below the industry average for depression trials. It's well below 10%. You know, you have over 90% of the patients that complete day 28. We have seen a pretty low dropout rate even in the long-term study.
We have now patients that have been taking the drug for well over 6 months, and the dropout rate is very low in the long-term safety study. Going back to the loading dose has been very well accepted. The pharmacology is very simple. REL-1017 has a long half-life. It's between 25 and 30 hours. That is a natural once a day therapy. It is highly binding to albumin, I believe, to the plasma protein. That implies the bioavailability is very high. It's well over 90%, so we have no problem with absorption. The profile is very clean, very easy to handle, very small molecule. If you take the regular dose, the steady state is at day four or five.
Taking loading dose is shorten the steady state at day two, three. That's the only reason there is the loading dose, to shorten, you know, the steady state of the plasma level.
Got it. Very helpful. Just final question, this one just came from a client. The question is: Do you have an opportunity to upsize any of these studies similar to what Janssen did, you know, if the blinded data are coming either below your expectation or different than what you might be assuming? Thank you.
That's a good question, and I don't have the direct answer. I would say no. I mean, 306 up to 364 patients, I believe is well, is a big number. Let me answer you in this way. That is probably the best way to answer. If the drug does not work well with 364 patients, then definitely we have done something wrong. We just don't see that going beyond that number would add any value.
Very well. Thank you so much. Really appreciate it.
Thanks, Yatin Suneja, for the question.
Our next question comes from the line of Marc Goodman with SVB Leerink. Please proceed with the question.
Yes. Hi. Sergio, I've gotten this question a couple times, so I figured I might as well just let you answer it, to everybody. I guess there's two of them. One is if the monotherapy study is positive and then one of the adjunctive studies is positive but the other is negative, what do you do next? What do you need to do? What's your understanding with the FDA? Second question is, if the monotherapy is positive or negative, help us understand what kind of read-through that is for the adjunctive studies. What does it mean, either way? Thank you.
Thank you, Marc, on the question. The first question is if two trials are positive and one doesn't work. Well, if the one mono and one adjunctive are positive, we will file. There are examples and one is Janssen with Spravato that had like five trials, three, I believe, three failed, two positive and the patient population was or the trial design was not the same as they still got approved. You know, ultimately, the difference between monotherapy and adjunctive therapy in the depression setting is different, but it's not critical enough that the FDA would not look. It's a lot and a lot will depend on how the data will look like.
If the third trial fails with a p-value of 0.51, that, you know, we do believe the FDA will take these aspects into consideration. If the data are good and the failure is not a total failure, it is a zero that we just don't see how that can happen, then I think we have a good chance even with two studies.
Well, Sergio, have you spoken to the FDA?
And the second que-
Have you spoken to the FDA at all about if the mono was positive and you have one of the adjunctive positive, like has that been a discussion point and they were open to filing with that?
No. Well, you know, the FDA, from whatever I'm seeing in the last few years from my interaction, or what I've seen, like with the FDA, they won't look. They won't tell you anything until you give them the full data. They will never tell you, oh, if you know, kind of indicating things like that. They will usually tell you know, "Go ahead, and then we'll discuss at the time of the NDA." No, we have not discussed with the FDA, but that's normal. We won't expect any real guidance on that. They want to see the data. They're very data-driven.
Yeah.
Sorry, what's the second question was?
The second question was.
The-
If the first study is positive or negative, what kind of readthrough?
Yes.
Does that help us? Like, help us understand what we would know better walking into the last two studies.
Yeah. We have data on as an adjunctive therapy. That's when we feel comfortable, confident that we'll show good results, right? Based on phase II and based on everything we have done to make the phase III to be a high quality 2022 standard for a trial for depression. If monotherapy is successful, then clearly would be a good indicator that at least that the trials have been conducted appropriately. It's the same team, so they do exactly the same thing for all the programs. I would read through the successful phase III monotherapy trial that the adjunctive could be, like, similar successful. The question is, what happens if the monotherapy fails? What can we do that?
Well, definitely it's not going to be a very, like, positive signal, but also, there is in the adjunctive setting, there is another drug. The only potential difference, again, we don't know. We will know it soon, but for now we don't know. If there is any synergy between a SSRI that by itself doesn't work well, but you add an NMDA channel blocker, then there is this synergy and you see the good result we have seen. If the monotherapy fails, would not mean much for the success of the adjunctive. I can give you the summary even if I'm a little biased, but if the monotherapy is successful, clearly the good signal, good sign for a potential success of the adjunctive.
If monotherapy fails, I would not draw the conclusion that adjunctive treatment will fail as well. You know, there is the role of the non-satisfactory effect of the base therapy alone, the SSRI or SNRI alone could be very different in the combination with an NMDA channel blocker. You know, I hope I gave you the answer the best way I could.
Yeah. Thank you. Maged Shenouda, could you just give us a sense of what spending is gonna be this year? Whatever you can disclose.
Sure. We haven't given, you know, a defined guidance, but you can target about $30 million-$35 million quarter mark.
Thanks.
Sure.
Maged, you always get the easy question.
Our next question comes in line of Joon Lee with Truist Securities. Please proceed with your question.
Good afternoon. This is Jason on for Joon. Thanks for taking our questions. I guess my first question is, you know, you saw strong durability in phase II. Do you have any plans to assess for durability of antidepressant effects in the ongoing phase III? I have a follow-up question after that as well.
Thanks for the question. You mean for durability beyond day 28, I assume. After day 28, the trial becomes open label. So we will have some moderate score numbers measured. You know, it is open label, so for the FDA that would mean nothing. In general, it would not be like a very strong data. Yes, we will have some data, but not that would be like a major indicator of anything. It's open label.
Okay, thanks. I guess sort of on business development-
Sorry, one more thing on that. The FDA has not required any efficacy data after day 28, so they're very happy. They consider day 28 as a long-term effect, chronic effect.
Okay, thank you. We'll keep that in mind. I was gonna ask about BD. Do you have any, you know, you expect any discussions with a potential BD partner once you have first positive phase III data hopefully mid-year? Is your plan sort of to just hold off on that until you have results from all the studies?
Yeah. Well, as you may imagine, we have in constant contact with potential partner and all the potential, the license or, you know, partners, they won't start to do work on a molecule on the program after phase III. They know very well what we are doing and, you know, they have done their own due diligence. We don't think that nothing will happen before at least the first phase III data readout. But they want to be ready after the data. If the data are very good, it can be competitive, then they wanna already have the work done. But we have Gino on board now that seems like he will help us out on making this kind of decision.
What I can tell you is that when a potential partner does real due diligence, it's a big distraction. It's not due diligence that takes a couple of days. We are talking about two months process. We have done it. It's right now, even if we want to, we won't have the, like, the bandwidth and the capacity to go through a serious due diligence process with any potential partner. I think we will postpone everything at least after the first phase III readout.
Okay. Thank you, Sergio.
Thank you.
Ladies and gentlemen, as a reminder to register for a question, press one followed by four on your telephone keypad. Our next question comes from the line of Vamil Divan with Mizuho Securities. Please proceed with your question.
Hi. Great. Thanks for taking my question. I think on the same theme of most of the other questions, just trying to get ready for this data here coming up. A couple questions I have. One, I don't know if you have disclosed or you can disclose sort of the number of patients that you've screened for the various phase III trials or any sense of sort of the screen failure rate that you're seeing. I know you put a lot of steps in place here to get the right patients. Just trying to get a sense of if that's been successful or not. Then I'm also curious, as you mentioned, you don't have the phase II data in monotherapy to kind of drive your powering assumptions.
Can you talk about sort of what your powering assumptions are for the monotherapy trial specifically and how it compares to what you've done for the adjunctive trials?
Sure. Good afternoon, Vamil. Yes, I believe we have disclosed, it's not these are not the figures and numbers what the screening failure rate. It is in line with the industry. It is between 50% and 60%, depending on the period and depending on the trial. That is in line. We have an extra, as you mentioned, we try to be as more effective in selecting patients that are affected by depression as possible. We use the as a second line of diagnosis, we use the SAFER interview. The SAFER interview, depending on again time and different trial, the further failure rate, meaning patient that gets SAFER but they are not randomized, it's another 10%-20%.
You can assume that out of 100 patients they get selected and go through the screening process about, you know, 35-40, they make it to randomization. That is in line, but with SAFER is probably a little bit below the industry average. We don't have. There's not a lot of data published, but we got that from our CRO. We are pretty strict in terms of selecting patients. Failure rate is that, a 50%-60% first round and another 10%-20% in the second round. The second question is on the powering of the monotherapy.
Well, we did not really have anything to look at direct in monotherapy, so we took the right way of just assuming the same assumption we did for as an adjunct, for the adjunctive therapy. The statistical plan, they are exactly the same. We do believe it's a fair assumption.
Okay. I think just to confirm, I think you said the powering is based on sort of getting a 2-point separation in combination. Is that correct?
Yes, that's correct. If the delta between drug and placebo day 28 is two points on the MADRS scale, the study will be statistically significant.
Okay. Yeah. I was gonna just follow up on that.
Worst case.
Do you have a threshold you'd say for what you think would be really sort of clinically meaningful results that you're looking for maybe beyond the two-point separation in either monotherapy or adjunct?
Well, we have to say what the industry and the FDA and the KOL tell us. The two points, it is clinically meaningful. It is going to change the way depression is treated. If we show two-point delta, probably not. It would be another antidepressant, will probably be approved, it will be used. But it's not going to be like what we are hoping to do, is to change, you know, the game changer in the treatment of depression. That two points won't make it. You know, three points and above, that would be different. That would make a big difference. The standard two points, it is considered clinically meaningful.
We do believe that for what we hope to do and we expect three points and above would be much better, much more clinically meaningful.
Okay. All right, great. Thanks for taking the question.
Thank you, Vamil.
Our next question is from the line of Jay Olson with Oppenheimer. Please proceed with your question.
Oh, hey, this is Matt on for Jay. Thanks so much for taking our questions. So the first thing we were wondering about, I guess, is just on any physician feedback that you might have received already on the HAP studies from the recent Ketamine and Related Compounds Conference. Just curious if some of that feedback includes how they view the safety and tolerability and abuse potential profile of REL-1017 versus generics or other NMDA antagonists in development.
Secondly, we were just curious, similarly if you've received any feedback on the publication on the Olney's lesions in preclinical data. As a corollary, if you're doing any scans in the phase III on human patients to detect any brain imaging abnormalities, that would be interesting as well. Appreciate that. Thank you.
Sure. Yeah, Matt, thanks for the question. The first question is the feedback from physician on the human abuse potential study. The answer is yes, we got a very confident feedback from KOLs and from whoever understands this data. One thing is that I can share is that nobody was really surprised by this data. The DEA has already made up their mind, and they make it on, it's on their website. The data we generated just confirmed what was already known by, you know, the abuse, if I can call, the abuse community. Nobody got really surprised by this data. Definitely the feedback has been very positive. It's been confirmed that, you know, the risk of, you know, the potential for abuse is not there.
That's one. On the Olney's lesions, there was more interest than at least I thought. But there are concerns about, you know, the Olney's lesions in the long-term use of NMDA antagonist. There's probably the background that was created by MK-801 that was potentially effective, but the toxicity was very high. The feedback was very positive that there is no risk of Olney's lesions. Consider that REL-1017 has a very long history in human through the racemic. That it means nothing in terms of efficacy and mechanism, but in terms of safety can give some indication. It's been in human for 50 years.
At very high doses, much higher than we're using, there's been no report of any brain damage of anything or any long-term effect in that case. In the phase III, to my knowledge, no, we are not doing anything in terms of MRI of any detection of brain damage. We don't expect any. There was no sign of any signal that there is a potential for any brain damage. We actually hope, based on everything we have seen so far and, based on the neuroplastic effect, we do believe that there is a potential for an improvement of brain function and, you know, dendrite functionality and the neural connection.
When there is a chronic strain, chronic stress can generate some form of dendrite atrophy. The brain can tend to. If you look at the brain of patients that are affected by depression for you know all their life or for many years, and there is some morphologic change in the brain structure. REL-1017 should show in if it's you know the patient start to take it early enough, it takes from long-term, could potentially, and I use the conditional here because we don't have the data, but based on the mechanism, could potentially improve the brain functionality, not only not to damage it.
Okay, got it. That makes perfect sense. Really appreciate that. The one other thing we were just wondering about, since it has not been asked yet is just, the current status of the, REL-P11 psilocybin compound. Just curious where that currently stands and any, thoughts on, next steps of development and potential indications. Thanks so much.
Yeah, sure. We keep a low profile on the psilocybin for a few reasons, main one is we are really busy with the REL-1017 program. You know, the psilocybin is moving nicely forward. I believe we're finishing up the manufacturing process. I don't know if we disclose it or not, but I'm going to disclose it anyway. We will make psilocybin with a proprietary synthesis. So we won't buy it. We make it ourselves. It's economical and you can have as much as you want, and it's much cheaper than buying from third parties. When that is finished, we will update the community on the next step.
We are doing also a certain number of preclinical studies and the goal of the preclinical studies is to show, and the FDA wants to see it, to show and confirm that psilocybin that is a 5-HT2A agonist has a neuroplastic effect as well. It's being currently tested in animals, I believe rodent, zebrafish and I believe some form of fly with, you know, there are certain model that detect the neuroplastic effects of compounds. Preclinical ongoing and in manufacturing. The big difference will be, you know, and we will discuss with the FDA what kind of information, if any information they want to see on the preclinical and safety of psilocybin.
We're using a dose that is substantially lower than what everybody else in the psilocybin space is using. We're using it low dose chronic. That could play a role in our conversation with the FDA. If the information already available for psilocybin in terms of safety they are sufficient then, and I use the conditional again, then we may be able to go straight into a phase II. That would save a couple of years of time and would be like a catalyst that we will have data probably 12 months after we start the phase II. Too early to make, you know, big statement. We still have to see the results of the preclinical and you know finish the manufacturing and then discuss with the FDA.
Probably, we'll give an update toward year-end, after the phase III readouts.
Okay, got it. That makes sense. Thank you very much. Appreciate, you taking the question. Congrats on all the progress.
Thanks for asking.
Our last question is a follow-up from the line of Yatin Suneja with Guggenheim Securities. Please proceed with the question.
Hey, guys. Thank you for allowing the follow-up. Just quickly, can you provide a little update on the enrollment, especially on the monotherapy study? Just like where you are, how close to reaching full enrollment and could you narrow the timeline on the data or the current guidance stance?
Yeah. Thanks, Yatin. Well, narrow the timeline on the data, we stay with the median, so I would not go, you know, more into details. The reason that, you know, there are variables like the data cleanup and so it's impossible to really give very specific like week or even months. So we keep like a month plus minus as a buffer. In terms of enrollment is actually going very well. We took some measures earlier this year, and we brought on board an infrastructure that mimics the CRO. So we have our own medical liaison. They call MSLs. We have our own CRA, the clinical research associate, and they all go to site, and they follow the study, you know, very closely.
We do have also one or two people that do the data cleanup internally. We want to be ready and you know, try to speed up the enrollment and you know, the data read as fast as possible. At the same time, Yatin, as I'm sure you agree, we look at quality first, right? Enrolling patient in depression is very easy. You can find as many patients as you want. But you know, to find quality in term of the enrollment, it's a little bit more difficult. So we totally focus on quality. We want to get it right the first time, not the second. But enrollment, I can see that right. It's going very well.
Thank you.
There are no further questions at this time.
Okay. Well, thanks. In closing statement, I'm very grateful to the Relmada team for their continued hard work and dedication to executing on our mission. I also like to extend my sincere thanks to the participants, partners and clinical partners involved in the REL-1017 clinical trials for their efforts in advancing this important product candidate through the clinic as expeditiously as possible. With that said, I wish to everybody and everyone a wonderful end of the day and we'll speak soon or at the next quarterly call. Thank you very much.
That does conclude the conference call for today. We thank you for your participation and ask that you please disconnect your line.