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spk01: Thanks for having me.
spk08: Thank you, Operator, and thank you all for joining us this afternoon. With me on today's call are Dr. Sergio Traversa, Chief Executive Officer, and Megan Shenouda, Chief Financial Officer. This afternoon, Ramada issued a press release providing a business update announcing financial results for the quarter ended June 30, 2024. Please note that certain information discussed on the call today is covered under the Safe Harbor's 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. 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 Ramada'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 31, 2023, and with subsequent filings, including the second quarter 2024 10-Q filed after the close today. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast on August 7, 2024. 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 Sergio. Sergio?
spk05: Thank you, Tim, and thanks to everyone for taking time to join us this afternoon. Bermuda is dedicated to the development of transformative medicine for people living with central nervous system disorder. And I'm pleased to report that Bermuda's clinical program has made meaningful progress over the last five months. We believe that the portfolio led by the Phase III program for REL 1017 as a potential adjunctive treatment for major depressive disorder, or MDD, is poised to reach several important milestones. And we are encouraged by the company's progress. As a quick reminder, REL1017 is a small molecule that preferentially blocks a hyperactive brain channel called NMNDA receptor that is associated with MDT. REL1017 has been designed to rapidly improve symptoms and provide these patients with new treatment options on top of their current regimen. Completing the Phase III program for REL 1017 is RealMata's number one objective, and it will complete the study package required to file the NDA. During today's call, we will discuss the planned interim analysis, planned by year-end 2024, for the Reliance II study, review the timing to complete enrollment in the two Phase III studies in the REL 1017 program, outline timing to initiate a Phase I study for VAPA proprietary psilocybin program, RELP11, in development for metabolic diseases, and comment on our cash balance, which we expect to support our planned operation into 2025 and several key clinical milestones, especially for the RELP1017 program. I'll briefly review our program. And in a few minutes, Margaret will provide you with a summary of our second quarter financial. After that, I will make a few closing remarks, and then we will open the call for your questions. Starting with REL 1017. We are enrolling two pivotal phase three studies for REL 1017, Reliance 2 and Relight. These studies built on positive phase two data with REL 1017 for the adjunctive treatment of depression. Our clinical data set also demonstrated that REL1017 is well tolerated with no indication of abuse potential. Our ongoing Phase III studies are designed to assess the impact of REL1017 of the MADRA score as an indicator of depression severity. The studies are evaluating REL1017 in patients with documented clinical depression undergoing treatment with an approved antidepressant. Each of the ongoing studies, Reliance 2 and Relight, is enrolling up to 340 subjects. The studies are randomized one-to-one and designed and powered to detect two 2.5-point delta in the Madras score at day 28. The protocols have been thoughtfully designed to incorporate several elements intended to de-risk each study with a thorough patient adjudication process. As a snapshot, the features that we have emphasized in the Reliance 2 and Relight studies are focused on optimizing the protocol, carefully selecting study sites and monitoring the number of patients per site, and most importantly, carefully verifying the diagnosis of depression and each patient's medical history to ensure enrollment of patients with clinical depression. We have been especially focused on defining the patient enrollment criteria with extra care. The current protocols include a review of medical and pharmacy records. The studies also require that patients have been treated with an approved antidepressant for at least six weeks and have experienced an improvement of less than 50% since starting treatment. Adoption of these elements has increased our confidence that we are appropriately enrolling the most suitable patients into Reliance 2 and Reliant. As a result of these efforts, changing in the screen failure rate can be considered one way to assess the stringency of the enhanced enrollment criteria. As of today, we are observing an approximately 80% screen failure rate versus a 50% screen failure in the Reliance 1 studies. We intend to reach two important milestones by end of the year, reporting the output of a pre-planned interim analysis and completion of enrollment of Reliance 2. We expect completion of enrollment in real life to follow approximately six months after that. The pre-planned interim analysis of Reliance 2 study is intended to be a de-risking tool to increase the probability of a successful study outcome. The analysis will include a futility analysis and a sample size re-estimation, if necessary, with the potential to adjust the sample size to ensure proper statistical powering. There are three potential outcomes from the interim analysis. The study is futile, the study can continue with the addition of a certain number of patients, and the study can continue with the pre-planned number of patients. That, of course, is what would be our preferred outcome. We will conduct the interim analysis and expect to report the outcome of this analysis before year-end 2024. Now, I would like to spend a few moments on RELP11. We identified the metabolic activity of RELP11 as part of a preclinical evaluation on its potential effect on neurodegenerative disease. As a quick reminder, RAUP11 is a low-dose, modified-release formulation of psilocybin. Compelling data from a recognized preclinical rodent model of metabolic dysfunction-associated steatotic liver disease, or MASLD, published last year in November at the American Association for the Study of Liver Disease, is the cornerstone of our program. This data showed that RELP11 has a benefit on multiple metabolic parameters, including triglyceride levels and glucose metabolism. Besides reducing steatosis of the liver, RELP11 reduced blood, glucose, and body weight without producing any side effects on the CNS. This data led to our evaluation of P11 as a candidate for the treatment of metabolic disorders such as obesity. We plan to initiate a Phase I single-accent dosing, or SAD, study in this subject for RELP11 shortly. The Phase I study will define the pharmacokinetic safety and tolerability profile for RELP11 and allow us to select a dose for evaluation in the Phase IIa proof-of-concept study. We expect to complete the Phase I SAD study and initiated Phase 2A study in H1, first half of 2025. Now, I would like to turn the call over to our Chief Financial Officer, Maga Shenouda, to review our recent financial results.
spk09: Maga? Thank you, Sergio. This afternoon, we issued a press release announcing our business and financial results for the three and six months ended June 30, 2024. During today's call, I will provide a brief overview of the three-month financial results. Full details are available in our press release and 10-Q filing on our website located in the news and SEC filings tabs of the investor relations page. Research and development expense for the three months ended June 30, 2024 were approximately $10.7 million compared to $13.7 million for the same period in 2023. a decrease of $3 million. The decrease was primarily driven by a decrease in study costs associated with the completion of two Phase III trials and the long-term open-label safety Reliance III trial or Study 310. General and administrative expense for the three months ended June 30, 2024, were approximately $8.1 million compared to $12.3 million for the same period in 2023. a decrease of approximately $4.2 million. The decrease was primarily driven by a decrease in stock-based compensation expense. The net loss for the three months ended June 30, 2024, was $17.8 million, or 59 cents per basic and diluted share, compared with a net loss of $25.3 million, or 84 cents per basic and diluted share, for the same period in 2023. I will also note that the company had 30.17 million common shares outstanding as of August 2nd, 2024. As of June 30, 2024, RealMata had cash, cash equivalents, and short-term investments of approximately $70.4 million compared to $96.3 million as of December 31, 2023. Cash use and operations for the second quarter was $13.3 million. Based on our current clinical development plans, we believe our current cash position is adequate to support operations into 2025 through key milestones, including the top-line data from the Reliance 2 study. Before we go to your questions, I'll turn back to Sergio to make a few closing comments. Sergio?
spk05: Thank you, Megan. As we conclude the prepared remarks on this afternoon's call, I would like to leave you with a few key messages. Our two phase III studies for our lead program, RELS 1017 for MDD, has been thoughtfully designed and are being carried out with appropriately adjudicated patients with potentially the risk, the studies. We expect two important milestones from the Reliance II study before the end of the year. With the output of a pre-planned interim analysis, which includes both a futility analysis and a simple size re-estimation, if necessary, and the completion of enrollment of the Reliance II study. We expect completion of enrollment of Reliance to follow approximately six months after that. Preparation on track to begin the clinical program for RELP11, our proprietary psilocybin formulation for metabolic disorders, later this quarter or early next quarter. We believe our financial resources will support our planned operations into 2025 through key milestones, including top-line data from the Reliance Study.
spk03: At this point, operator, we can open the call for questions. Hello, operator, are you there?
spk01: Apologies. And ladies and gentlemen, we will now begin the question and answer session. To ask a question, you may press the star followed by the number one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press the star followed by the number two. One moment, please, for your first question. Your first question comes from the line of Mark Goodman with Learing Partners. Please go ahead.
spk04: Thanks for taking my question. This is Rudy on the line for Mark. Okay, can you remind us the baseline measures for an ongoing RE-LINDS-II study and how that compares with the Phase II Gen-T MDD trial and the Phase III RE-LINDS-I study? Thanks.
spk05: Thank you for the question. Madras average, when the patient's population starts, they're very similar. It's right in the mid-30s, like 33, 34 range for all the studies. That's pretty typical for depression studies.
spk03: Got it.
spk04: Yes, just a quick follow-up. We'll give you the confidence that relying We're finishing enrollment six months after Reliance 2, and would a potential sample size re-estimation impact the timeline for that trial?
spk05: Yeah, well, the confidence, when Reliance 2 will be over, and if successful, as we hope, then all the resources will be put on Reliance, so we have, like, close to 100 sites that will be available. Of course, we may not involve all of them. So the full resource is dedicated to the studies. And so we do our confidence that based on the enrollment rates that we are seeing now, we can finish in about six months. And sorry, the second question was how we're confident about the timelines for the sample size re-estimation.
spk04: No, I was asking whether the sample size re-estimation will impact the timeline for the second trial.
spk05: That's a good question. Well, we will address it when we know how many patients we have to enroll, but it could, but it's probably not going to be very material. When we are talking about sample size re-estimation, we are not talking about adding like 200 patients to the study. that would be probably a problem in general. And so sample status re-estimation will evaluate how many if and how many patients will have to enroll. Got it.
spk03: So the answer to your question is that it may, but it's not going to be a material timeline change. Very helpful.
spk02: And your next question comes from the line of Andrew Chai with Jefferies. Please go ahead.
spk03: Andrew, you might be on mute. Andrew Chai? Hi, can you hear me? Yes, now yes.
spk07: Yes. Hi. Thanks for taking my question. So on clinical trials, we noticed there are some changes to the estimated patient enrollment number to 340. I think you mentioned it in the prepared remarks. So can you talk about why that number changed from 300 to 340? Yeah, sure. Good afternoon, Andrew.
spk05: Well, clinicaltribe.gov is more a general, like, indication that is made mostly for the FDA, and it's an indication, right? The patient population would be up to 340. That doesn't mean that we'll go to 340. You don't want to change, like, the update clinicaltribe.gov too frequently, and so you put some guidelines that, you know, you expect to be meeting, and also you have to, like, depends if you include dropouts and non-dropouts, but the number of patients is up to 340. That doesn't mean that we have to go to 340, assuming no sample re-estimation. I would not take that as the final number. The final number would be determined by the statistical plan that we have not finalized. You usually send to the FDA the statistical plan as close to the end as possible because there is no upside in defining numbers before depends on the enrollment rate and values parameter. So I hope I answered your question. I don't take the 340 as the final absolute number. It's up to 340.
spk07: Got it. Yep, very helpful. And it sounds like there's a futility analysis in the interim now. So did you have to change the protocol or the stats plan? And are you taking any statistical penalty with the futility option?
spk05: Well, thanks, Andrew, for asking the question because it's very important. And we did spend the last, I would say, couple of months to work on the statistical plan. And I'll tell you why. Because when we had in the study 301, we had an interim review. And what we get from the data monitoring committee is was like stop the trial as early as possible. But we had absolutely no indication of what was the reason for that. Could have been futility or could have been efficacy. And that one was actually, didn't really help Ramada because we stopped it as indicated at the earliest. There was like 220, it was 2027 patients. And there were, the results were not the one we were expecting. If we would have gone to the 300 plus that was the plan, maybe the study based on the numbers could have been statistically significant, especially because the second part of the trial was conducted when the COVID restriction were lifted. And you may remember that the results of the last 63 patients enrolled in 301 were actually very, very good compared to the previous 165 patients. So that interim analysis was not only not very helpful, it actually created a little bit of a problem. So this time, we don't want to end up in the same situation. So we have been very carefully planning the interim analysis. And we want, within the boundary of what can be done, of course, we want to get some information that can help to the risk, the problem. And so we inserted the futility analysis. So at least we want to know, we hope not, but we want to know if the study is futile, then we may decide if it is not the case to continue to preserve the cash that we already have. It is significant, the cash that we have already in our hands. And then there is a second scenario that is temporary estimation. The DMC will give us an indication how many patients we should add to get to a likely p-value. Then there is the third scenario that is the one that everybody likes the most. They will tell us that we can stop the trial at the planned number of patients. It would be around the 300, 310, or whatever. The final number would be defined in the statistical analysis and statistical plan. And we will know if that would be what the DMC will tell us. We will know that the study is not futile, because if it is futile, we will be informed, and that we don't have to add any patients to get to a potential p-value. There's no guarantee that the study was successful, because we may have some more patients to add that they are not incorporated in the statistical analysis at the interim, but clearly would give some good sense that we are on the right direction. And the last of your question was the statistical penalty. No, there is no alpha penalty in the futility analysis because there is no analysis on the efficacy and there is no early stop. So you don't pay any alpha penalty. I hope that was a long answer, but I wanted to be very clear and specific on this.
spk07: Yep, thank you. Very last one is, what would be the threshold for futility if the placebo-adjusted delta is below a certain point on the address, or do you have any color on that?
spk05: Yeah, that's a more difficult answer, not because we don't want to, but we haven't finished or finalized the analysis. And then we get into the, like, heavy, complicated statistics, but in general, our we will set the futility close to what can be a non-clinically meaningful threshold, right? If the study would not have a chance to reach any clinically meaningful result, then probably would not be worth to continue. But we haven't finalized what the numbers will be.
spk03: Thank you again. Thank you, Andrew.
spk01: And your next question comes from the line of Andrea Tan with Goldman Sachs.
spk00: Please go ahead. Good afternoon. Thanks for taking the question. Sergio, just really quickly, can you remind us the extent of the trial that you expect to be completed ahead of the interim analysis? And following that, how soon after that could we expect to see the top line data?
spk05: Let me be sure I understand. Hi, Andrea. Good afternoon. Let me be sure I understand. Your question, do we do have another trial before the interim analysis? No, the only two trials that are ongoing for REL 1017 is Reliance 2 and Relight. Everything else has been completed, long-term safety, they're all done.
spk00: Oh, no, I'm so sorry. I'm so sorry. I was just asking, in terms of the interim analysis that's being conducted or planned for Reliance 2, I guess maybe what proportion of that study is it? I think you may have mentioned in the past that it's around 80 to 90% of the trial, at which point the interim analysis will take place.
spk05: Yeah, I got it again. Sorry, I misunderstood. Theoretically, the later you do it, the better. Now, there is the incremental benefit that you get it going, like, let's say a 70 or 75, 80% become smaller and smaller. So we'll try to do it as late as possible, but we also want to know. And so it is going to be like before your end, right? Over the next, it's August. So the next, I would say three, four months. It takes a couple of months to prepare it. And so we are pretty close. We are pretty close.
spk00: Okay, and if the DMC advises that you could continue without additional patients being enrolled, maybe what is the expected timeframe over which we could then expect the top-line data?
spk05: Well, it depends on how many patients we'd have to enroll, but it's not going to be that far away. I don't have the exact number, but we are planning to finish and roll by your end, so you can imagine that. It can be by your end or sometime early 2025, but not too long after. If they tell us that we don't need to enroll any more patients, as we hope, it's going to be pretty short after that.
spk00: Okay. And then one quick question on the psilocybin study. Just curious if you could speak to the decision to run that study in Canada. And if that reflects any regulatory hurdles in the U.S., or maybe even a variation in how the different agencies view psilocybin?
spk05: Yeah, well, we do it in Canada for two main reasons, right? One is that Canada, for some reason, they have very good structure for Phase I. Just to give you an example, REL 1017, Phase I was done in Toronto in Canada because they have very good facilities. And the second one is that the Canadian agency, it is very used to psychedelic and is used to more than the FDA. So the regulatory hard rules are easier in Canada than in the U.S. So the combination of these two reasons made us do it in Canada. Nothing else, right?
spk00: Got it.
spk01: Okay. Thank you so much.
spk05: Thanks to Andrea.
spk01: And your next question comes from the line of Oiir with Bizot Financial Group. Please go ahead.
spk06: Hi. Thanks for taking my question. This is Charles on for Oi. I guess I had a question on the re-estimation analysis. Just I guess kind of dig into how many more patients you might add potentially in this analysis. Is that kind of a preset number or will they give you that number? And then also on the runway guidance, Is the runway still expected to read out for relight as well? Thank you.
spk05: Thank you, Charles. I will, Maggie, answer the second question. But the first one is the number will be recommended by the DMC. And so it can be anywhere, right? Clearly, if the target number is somewhere north of 300, And we don't expect to double that number of patients or to add like 200 patients. That would be an indication that the signal may not be that strong. So it would be a reasonable amount of patient that is also feasible in a reasonable amount of time.
spk03: Yeah.
spk09: And Charles, thank you for the question. I'll take the, you know, the financial, the finances question. You know, I don't think we want to get that specific with regard to, you know, the readout from the Relight study. What we have said is it will take us into 2025, certainly with data from the Reliance 2 study. And then a lot depends on enrollment patterns, and that's, you know, developing day by day. So, you know, I can't be that specific at this point.
spk03: Thank you for taking my question. Are there any more questions? Doesn't seem there are any more questions. Well, I assume there are no more questions pending.
spk05: And so we are not showing any more questions. I can go to the closing remarks.
spk01: Yes, presenters. Apologies. We don't have any questions at this moment. You can now proceed with your closing remarks.
spk05: Okay. Well, thanks a lot. And so thank you, everyone, for joining us for the RealMada second quarter 2024 conference call today. We believe we are poised to achieve several important milestones that could represent an inflection point for RealMada. We look forward to updating you on our progress, and thank you for joining us for this second quarter business update call. Have a great night.
spk01: Thank you, presenters. And ladies and gentlemen, this concludes today's conference call. Thank you all for participating. We now disconnect.
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