Relmada Therapeutics Inc (RLMD) 2022 Q1 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Relmada Therapeutics, Inc. First Quarter 2022 Earnings Call. (Operator Instructions) As a reminder, this conference is being recorded, Thursday, May 5, 2022.

I would now like to turn the conference 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 3 months ended March 31, 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 provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, Relmada's management team will be making forward-looking statements. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in Relmada's press release issued today and the company's SEC filings, including in the annual report on Form 10-K for the year ended December 30, 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 5, 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 time lines 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 we will take then 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 midyear for the ongoing Reliance Phase III trial. Specifically, we anticipate completing the enrollment of Reliance III, the ongoing monotherapy registrational Phase III trial, followed by top line data readout by midyear 2022 and followed by top line results from Reliance I and Reliance II. These anticipated time lines remain unchanged from prior guidance.

As a reminder, Reliance I and Reliance II are 2 ongoing Phase III system, 2-arm, placebo-controlled, pivotal studies evaluating REL-1017 25-milligram as a potential adjunctive treatment for MDD. Reliance III is the ongoing Phase III 2-arm, placebo-controlled, registrational study evaluating REL-1017 25-milligram as the potential monotherapy treatment for MDD. All participants in the Reliance trials take a loading dose on day 1 of 75-milligram. That is 3 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 2 HAP studies were consistent and confirmed the 2019 DEA statement on this method that states, that the d-isomer lacks significant respiratory depression action and addiction viability. We believe that oxycodone comparative data significantly derisked the Schedule II potential for REL-1017. And then the ketamine comparison data significantly derisked the drug candidate's Schedule III potential.

As we have said previously, we believe that the data generated to date from our growing development program indicates that REL-1017 could be initially proposed as a Schedule V drug with potentially to eventually a nonscheduled drug following 1 or 2 years of marketing SPA.

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 mid-year. Reliance III aims to randomize up to 364 patients who have been diagnosed with depression and are not currently taking standard antidepressant. The study includes 2 arms, placebo and 25-milligram REL-1017. Patients may have tried no more than 1 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 2 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 1 and up to 3 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 at day 7 and change in the Clinical Global Impression Severity scale, the CGI-S 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 enrolled in both. Rollover participants from all 3 pivotal studies as well as the de novo participants. RELIANCE-OLS is ongoing and continues to involve 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 and Strategic Adviser. He is a veteran and 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 roles, working in 3 different continents and in various areas of the pharmaceutical value chain. He is a former member of the executive team of 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 companies. 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 we have presented last month in 2 poster presentations and 1 oral presentation at the Ketamine & Related Compound 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 NMDAR locals. In REL-1017 treated rats, early Olney's lesions, which usually appears 1 day after treatment with MK-801, that is another NMDAR 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 that while we are so -- we are so passionate about advancing our (inaudible) at Relmada. To mark the occasion and increased visibility around mental health, we are participating in a number of initiatives this month, including sponsoring the 33rd Annual Lifesaver's Gala 2022 that is hosted by the American Foundation for Suicide Prevention. Several members of our team will be participating in local works 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 3 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, the REL-1017.

Noncash 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 noncash 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, cash equivalents and short-term investments of $220.6 million compared to cash, 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?

(Operator Instructions) Our first question comes from the line of Andrew Tsai with Jefferies.

The first question is actually on the kinetics of the Phase III monotherapy data coming out. It also applies to the adjunct study. So I guess my question is, how do you foresee the curve to look like for esmethadone, in particular, as well as placebo from day 7 to day 28? Should we be expecting no kind of rebound in terms of the efficacy? Or is some rebound actually okay in your view?

Well, thanks, Andrew. It's 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 experienced or we have data from other compounds that also work on the NMDA channel. So just based on what we have seen from Phase II and based on what is the experience from other similar compound, we don't expect any loss of efficacy over time actually based on the mechanism and if we do believe -- and we do believe the neuroplastic effect, then longer term, the efficacy of the drug should just improve. So we're not expecting a loss of efficacy after day 7. We expect to be stable and, hopefully, better than day 7.

Right. Okay. Very good. And secondly, it's more of a high-level question, maybe more open ended, is just, I guess, conceptually, what do you guys think you've done for these Phase III studies to maximize their probability of success? What are you doing differently than the other companies with depression programs, anything in the inclusion criteria or COVID protocols, 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. But top down, we have done everything that 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 strong statement without the data. But based on Phase II, we do believe the drug is safe. It's well tolerated, but also that the drug works, has a very strong efficacy. And so we don't see any reason why the drug should not confirm the same effect in the Phase III program.

What is the potential risk or what everybody is afraid in every trial, but especially in depression trials, the placebo effect. So 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 site with experience in depression clinical studies, rater selection. The raters are actually trained by a company that is called CT&I. 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. And so from the site, the raters, the -- 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 support -- be sure that the patients -- the compliance that the patients take the drug, that's a little video that is uploaded every day showing that the patient is taking the video -- is taking the tablets.

Reading a statement, we -- every MADRS interview that the patient has to read the statement that have 50% chances to be on placebo upon -- that produces the placebo effect and so on, right? There is no magic. There is no magic bullet of a strategy that can guarantee you the results. But we do believe that all we have done so far to support quality of the patients, compliance and should support, right, a good control of the placebo effect. Long answer, but I hope I answered your -- I want to answer in a little bit more detail.

Yes, I think that you did. Right, I think it's important. Yes, and then very last question is in addition to kind of monitoring for 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. And then are you able also to confirm the DMC committee is still seeing no signs of opiate or dissociate effects?

Yes, yes. I answer first the second question. It is easier. Yes, the DMC is not -- I mean, from the last meeting of the DMC, and they are stating to continue as planned, we have not heard anything different about any severe side effect or any change in the program. And yes, the answer is yes. If there were anything that would suggest to change something in the study, that will also mean if there is withdrawal symptoms or anything that is unusual that would pose any risk for the patient, then we would have known. So we assume that from the review, there was no sign of any [developed] effect. And remind me the first question as I lost a little bit of (inaudible).

If you're seeing anything -- right, if you're seeing anything else on a blinded basis basically.

Yes, I'm not trying to avoid it. No, look, the blinded data, they are extremely useful for safety. Then if there is no sign of any severe side effect, you assume that -- we assume that placebo does not give severe side effect. We have seen nothing. So it's a fair assumption that the drug is safe and well tolerated. On the efficacy, it would be highly risky to look at blinded data and to make any statements. Until you know what the placebo does, it's impossible to draw any conclusion. Probably, we would see if there is 0 effect, right? If everything would be a 0, you assume that nothing is working, so the drug would not work. But that's all you can tell. So we don't believe we will see a 0 effect, but that's not an indication of any final results. So we have to be a little patient here.

Our next question comes from the line of Andrea Tan with Goldman Sachs.

Sergio, maybe just 2 for you. Just curious if you could speak a little bit more on your estimates of the size of the monotherapy opportunity. And then do you envision positive data from Reliance III could prompt inclusion on REL-1017 label? Or do you think you would need to run an additional study and submit a supplementary filing thereafter?

Thanks, Andrea. Thanks for the question. Well, the -- moving forward, in the next call, we will be probably more precise on the size of the market and, with Gino on board, one of the role of the health will be to -- will give 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 will be the big difference because competition in adjunctive treatment, there is no antidepressant approved. There are only 3 drugs and they're all antipsychotics. So that makes the task not easier but definitely a little bit more favorable because if REL-1017 makes it to the market as an adjunctive treatment, that would be the only antidepressant available. And so there is going to be more price power and less competition, direct.

Monotherapy, the competition is generic, 26, 27 drug with an exception that I believe is [3,000]. It's the only brand that's antidepressant left. And so price will be critical, price competition. Price competition can only be overturned by one factor. It's 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 an effect size about 0.3, and they work in about 30% to 40% of the patients, take a month at least, to show any efficacy. And 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 1 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 nonresponder to traditional antidepressant, response rate was very close to 60%. So 6 out of 10 patients responded. And that's going to be very difficult for payers to recommend as the frontline traditional antidepressant.

So the clinical data will really drive the size of the market. And price will be a very important factor. It will be more -- like towards the next few months, we will work more closely with the payers. And we will have a better understanding of what they want to see to make -- to put REL-1017 as a front-line therapy, even it's 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 somehow grouped into an existing label for the adjunctive use case.

Yes. Well, we -- to be direct, we did not address with the FDA these aspects. The FDA was in line with running a Phase III instead of a Phase II. So that could be read as a positive indicator. But again, the data will drive -- the data will be compelling. We don't see any reason why we should have to run a second monotherapy trial. And if the 2 adjunctive trial would be positive, right, we go to the FDA with 3 trials, with compelling data, positive, plus the long-term safety that doesn't show any issue. We've kind of seen that there is the potential for -- the risk for abuse doesn't seem to be there at all. So that would be a very powerful package for the FDA. So yes, if everything goes the way we hoped and we think that the 3 trial will be successful or we won't see any safety risk, then we assume that we won't have to run a second Phase III monotherapy trial. We don't think we can add any more information on what is already available.

(Operator Instructions) And our next question comes from the line of Yatin Suneja with Guggenheim Partners.

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 4-week time frame? Because in your study so far, we've just seen 2-week data. So 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 has been -- is a critical topic that we have really talked about from every different angle. Let me give you the numbers that we talked about putting into the statistical model. So in clinic, in patient treatment, they tend to have a higher placebo effect. So there is an advantage in running an outpatient trial the way we are doing with the Reliance program.

At the other side, our Phase II was 7 days treatment, so placebo was taken for 7 days. Placebo tend to have a gradual increase over time for a variety of reasons. So we do believe that these 2 factors, they balance themselves, right? If you look at the placebo effect in Phase II, it was, I believe, if I remember correctly, 8 points after 7 days. That's a pretty high placebo response. We have seen a number in other trials that go from 4, 5, 6. So they tend to be lower in an outpatient setting. So the inpatient played a role, and the placebo effect was higher than in outpatient.

In the assumption, then now we have a trial with 4 weeks. I think the number -- in the statistic (inaudible), we assumed that the placebo will be 12 points. So if the placebo delta from baseline to day 28 will 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 it will be very, very, very successful.

If the placebo performed from baseline above 12 points, it depends. It is 13, 14, it's still manageable. We do believe the trial will still be successful. If it is above 15, I don't see much. I haven't seen many of these. I don't see these numbers. But if placebo is above 15, then we have a problem. So you can assume that 12 points 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. If it is very slightly above, we'll still be successful.

Got it. Right. Very good. Then can you confirm if patients in all 3 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? And then also, 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 3 studies are taking the loading dose. I do believe that also for new patients, also the long-term safety study starts with the loading dose, that it is 75 milligrams. It's 3 tablets. I'm happy to share that even taking 3 tablets the first day, we have seen nothing in terms of serious, severe side effect. That is confirmed by the discontinuation of the dropout rate that is well below the industry average for a depression trial. So it's well below 10%. And so you have over 90% of the patients that complete day 28. And we have seen a pretty low dropout rate even in the long-term study. We have now patients that are -- have been taking the drug for well over 6 months, and the dropout rate is very low in the long-term safety study.

So going back to the loading dose, has been very well accepted. The pharmacology is very simple. REL-1017 has a long (inaudible) life. It's between 25 and 30 hours. That is a natural once-a-day therapy. It is highly binded to (inaudible) to the plasma protein. So 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. And the -- if you take the regular dose, the steady state is a day 4, 5. Taking the loading dose will shorten the steady state at day 2, 3. So that's the only reason there is the loading dose, to shorten the steady state of the plasma (inaudible).

Got it. Very helpful. Then just final question. This one just came from a client. And the question is, do you have an opportunity to upsize any of these studies similar to what stage that if the blinded data are coming either below your expectation or different than what you might be assuming?

That's a good question, and I don't have the direct answer. The -- I would say no. The -- no. I mean up to 364 patients, I believe it's well -- it's a big number. Let me answer you in this way. That is probably the most -- the best way to answer it. If the drug does not work out with 364 patients, then definitely, we have done something wrong. So we just don't see that going beyond that number would have any value.

And our next question comes from the line of Marc Goodman with SVB Leerink.

Yes. Sergio, I've gotten this question a couple of times so I figured I might as well just let you answer it to everybody. I guess there's 2 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, Marc, on the question. So the first question is if 2 trials are positive and 1 doesn't work, well, if the 1 mono and 1 adjunctive are positive, we will file. There are examples and one is J&J with Spravato that had like 5 trials, 3 failed, 2 positive, and the patient population was -- or the trial design was not the same as they still got approved. So ultimately, the difference between monotherapy and adjunctive therapy in the depression setting is not -- it is different, but it's not critical enough that the FDA would not look. It's a lot -- a lot will depend on how the data will look like. If the third trial fails with a p-value of 0.51, we do believe the FDA will take this aspect in consideration. So if the data are good and the failure is not a total failure, it is 0, we just don't see how that can happen, then I think we have a good chance with 2 studies. And the second question...

Well, Sergio, 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 a filing with that?

No. Well, look, the FDA, for whatever I've seen in the last few years with my interaction or what I've seen with the FDA, they won't look -- they won't tell you anything until you give them the full data. And so they will never tell you if you're kind of indicating things like that. They usually tell you go ahead and then we'll discuss at the time of the NDA. So 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. And so the second question was?

The second question was if the first study is positive or negative, what kind of read-through does that help us? Like help us understand what we would know better walking into the last 2 studies.

Yes. So the -- we have data on -- as an adjunctive therapy. So that's one we feel comfortable -- confident that will 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 depression. Now if monotherapy is successful, then clearly would be a good indicator that at least the trials have been conducted appropriately. It's the same thing. So they do exactly the same thing for all the problems. So the -- I would read through the successful Phase III monotherapy trial that the adjunctive could be similar, successful.

Now the question is what happens if the monotherapy fails, what can we do then? Well, definitely, it's not going to be a very positive signal, but also there is -- in the adjunctive setting, there is another drug. So the only potential difference, we don't know. We will know it soon, but for now, we don't know. If there is any synergy between SSRI that by itself doesn't work well, but you add an NMDA channel blocker, then there is a synergy, and you see the good results we have seen. Then if the monotherapy fails, it will not mean much for the success of the adjunctive.

So I can give you the summary even if I'm a little biased, but if the monotherapy is successful, then clearly there's a good signal, good sign for a potential success of adjunctive. If monotherapy fails, I would not draw the conclusion that the adjunctive treatment will fail as well. There is -- the role of the nonsatisfactory effect of the base therapy alone, the SSRI alone could be very different in a combination with NMDAR channel blocker. I hope I gave you the answer the best way I could.

Maged, can you just give us a sense of what spending is going to be this year, whatever you can disclose?

Sure. We haven't given a defined guidance, but you can target about $30 million to $35 million a quarter, Marc.

Our next question comes from the line of Joon Lee with Truist Securities.

This is [Austin] on for June. So I guess my first question is, you saw strong durability in Phase II. Do you have any plans to assess for durability of antidepressant effects in the ongoing Phase III? And I have a follow-up question after that as well.

Thanks for the question. For durability, you mean beyond day 28, I assume. Well, we will -- after day 28, the trial becomes open label. So we will have some MADRS score numbers measured, but it is open label. So for the FDA, that would mean nothing. And in general, it would not be like a very strong data. So yes, we will have some data, but not that will be like a major indicator of anything. It's open label. Sorry, one more thing on that. The FDA does not require any efficacy data after day 28. So they're very happy. They consider day 28 as a long-term effect, chronic effect.

Okay. We'll keep that in mind. So I was going to ask about BD. Do you have any -- you expect any discussions with a potential BD partner once you have first positive Phase III data, hopefully, midyear? Or is your plan sort of to just hold off on that until you have results from all the studies?

Yes. The -- well, as you may imagine, we already have -- we have in constant contact with potential partner and all the potential -- the licensed 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 they have done their own due diligence. We don't think that nothing will happen before the -- at least the first Phase III data readout. And the -- but they want to be ready after the data. If the data is very good, it can be competitive. Then they want to already have the work done. But we have Gino on board now that is the -- 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 2 months process. And we have done it. So it's -- right now, even if we won't have the -- like the bandwidth and the capacity to go through a serious due diligence process with any potential partners, so I think we will postpone everything at least after the first Phase III readout.

(Operator Instructions) And our next question comes from the line of Vamil Divan with Mizuho Securities.

So I think on the same theme of most of the other questions, just trying to get ready for this data here coming up. So a couple of questions I have. One, I don't know if you have disclosed or you can disclose 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. So I'm just trying to get a sense of if that's been successful or not. And 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. So 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. Vamil, the -- yes, I believe we have disposed of -- these are not material numbers, but 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. The -- we have an extra -- as you mentioned, we try to be more effective in selecting patients that are affected by depression as possible. And we use the -- as the second line of diagnosis, we use the SAFER interview. And the SAFER interview depending on, again, time and different trials, the further failure rate, meaning patients that get to SAFER, but they are not randomized, it's another 10% to 20%.

So you can assume that out of 100 patients that get selected and go through the screening process, about 35 to 40, they make it to randomization. That is in line, but with SAFER, it's probably a little bit below the industry average. We don't -- there's not a lot of data published, but we got that from our CRO. And so we are pretty strict in terms of selecting patients. Failure rate is at 50% to 60% first round and another 10% to 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 directly monotherapy. So we took the way of just assuming the same assumption we did for the adjunctive therapy. So the statistical plan there is exactly the same. And we do believe in the same assumption.

Okay. And I think just to confirm, I think you said the powering based on sort of getting a 2 point separation in combination, is that correct?

Yes, that's correct. So if the delta between drug and placebo day 28 is 2 points on the macroscale. The study will be statistically significant. We hope (inaudible) further than that, but (inaudible) worst case...

Yes. I was just going to follow-up on that. Do you have a threshold to, say, for what you think would be really sort of clinically meaningful results that you're looking for maybe beyond the 2-point separation in either monotherapy or...

Well, we have to say what the industry and the FDA and the KOL tells us. 2 points, it is clinically meaningful. It is going to change the way depression is treated. If we show 2-point delta, probably not. It would be another antidepressant. It will probably be approved with our BUs. But it's not going to be like the -- what we are hoping to change the game changer in the treatment of depression. 2 points won't make it. 3 points and above, that will be different. That would make a big difference. So the standard, 2 points, it is considered clinically meaningful. We do believe that for, what we hope to do and we expect, 3 points and above would be much better, much more clinically meaningful.

And our next question is from the line of Jay Olson with Oppenheimer.

This is Matt on for Jay. 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 & Related Compounds Conference. I'm 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 antagonist in development. And then secondly, we were just curious, similarly, if you've received any feedback on the publication on the Olney lesions in preclinical data. And as a corollary, if you're doing any scans in the Phase IIIs on human patients to detect any brain imaging abnormalities, that would be interesting as well. Appreciate that.

Sure. Matt, thanks for the question. So the first question is the feedback from physicians on the human abuse potential studies. Yes, we got a very, very confident feedback from KOLs and from whoever understands this data. And one thing is that -- I can share is that nobody was really surprised by the data. The DEA has already made up their mind and they make it on their website. So the data we've generated just confirmed what was already known by the abuse, if I can call the abuse community. And so nobody got really surprised by this data. But definitely, the feedback has been very positive. It's been confirmed that the risk of -- the potential for abuse is not there. So that's one.

On the Olney's lesion, that one was -- we got more -- there was more interested than I thought. And -- but the -- there are concerns about the Olney's lesion in the long-term use of NMDA antagonist. This probably is the background that was created by MK-801 that was potentially effective, but toxicity was very high. So we have been -- the feedback was very positive that there is no risk of Olney's lesion.

Consider that REL-1017 has a very long history in human through the (inaudible) that if it means nothing in terms of efficacy and the mechanism, but in terms of safety, it 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, no, we are not doing anything in terms of MRI or any detection of brain damage. We don't expect any -- there was no sign or any signal that there is a potential for 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 then drive functionality and that in connection -- when there is a -- chronic stress, can generate some form of dendrite atrophy. So the brain tend to -- if you look at the brain of patients that are affected by depression for all their life or for many, many years, and there is some morphologic change in the brain structure. So REL-1017 should show in -- if it's -- the patients start to take it early enough, takes it for long term, could potentially -- and they use a 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. And the one other thing, we were just wondering about since it has not been announced yet, it's just the current status of the arbormentis psilocybin compound. Just curious where that currently stands and any thoughts on next steps of development and potential indications.

Yes, sure. We keep a low profile on the psilocybin for a few reasons, but the main one is we are really busy with the REL-1017 program. But the psilocybin is moving nicely forward. I believe we are the manufacturing -- finishing up the manufacturing process. I don't know if we disclosed it or not, but I'm going to disclose it anyway. The -- we will do -- make psilocybin with a proprietary synthesis. So we won't buy it. We'll make it ourselves. And that is the -- it's economically and you can have as much as you want and it's much cheaper than buying from third parties.

And so when that will be finished, then 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-H2A (sic) 5-HT2A agonist has a neuroplastic effect as well. And so it's being currently tested in animals. I believe rodent, zebrafish and some form of fly where there are certain model that detect the neuroplastic effect of compounds. So preclinical, ongoing and in manufacturing. The big difference will be -- 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 on what everybody else in the psilocybin space is using. And we're using a low-dose chronic. And so that should -- could play a role in our conversation with the FDA.

And if the information is 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 a catalyst that we will have data probably 12 months after we start the Phase II, but too early to make a big statement. We still have to see the results of the preclinical and finish the manufacturing and then discuss with the FDA. Probably we'll give an update toward year-end after the Phase III readout.

And our last question is a follow-up from the line of Yatin Suneja with Guggenheim Partners.

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 time line on the data or the current guidance stands?

Yes. Thanks, Yatin. Well, narrow the time on the data, we stay with the media. So I will not go more in detail. And the reason's that 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 enrolling, it's actually going very well. We took some measures earlier this year, and we brought on board an infrastructure that mimic the CRO. So we have our own medical liaison. They're called MSLs. We have our own CRA, the clinical research associates, and they all go to site and they follow the study very closely. And we do have also 1 or 2 people that do the data cleanup internally. So we want to be ready and try to speed up the enrollment and 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. And -- but to find quality in terms of the enrollment, it's a little bit more difficult. So -- and we totally focus on quality. We want to get it right and the first time, not the second. But enrollment is going very well.

There are no further questions at this time.

Okay. Well, thanks. And in closing, closing statement, I am 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 and clinical partners involved in the REL-1017 clinical trials for the effort 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 for 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 lines.