Good afternoon. My name is Kathy, and I'll be your conference operator for today. At this time, I would like to welcome everyone to the Relmada Therapeutics, Inc. Third Quarter 2022 Earnings Call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you'd like to ask a question during that time, simply press the star followed by the one on your telephone keypad. If you'd like to withdraw your question, again, press star one. Thank you. Brian Ritchie, you may begin your conference.
Thank you, operator, and thank you all for joining us this afternoon. With me on today's call, our 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 and nine months ended September 30, 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 during this call that 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 ending December 31st, 2021, and subsequent filings. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, November 10th, 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 would like to turn the call over to Sergio. Sergio.
Thank you, Brian, as always, and good afternoon to everyone. I'm pleased to welcome you to the Relmada Third Quarter 2022 Conference Call. During today's call, I will provide an update on our ongoing late-stage RELIANCE clinical development program for REL-1017, our lead product candidate that we are currently studying as a novel treatment for patients with major depressive disorder or MDD. Following my comment, Maged Shenouda, our Chief Financial Officer, will review our financial results and balance sheet, and we'll then take your questions. As a reminder, RELIANCE I and RELIANCE II are two ongoing phase III sister two-arm placebo-controlled pivotal studies evaluating REL-1017 25 mgs as a potential adjunctive treatment for MDD.
RELIANCE III was the phase III two-arm placebo-controlled registrational study evaluating REL-1017 25 mg as a potential monotherapy treatment for MDD. We announced top-line results last month for RELIANCE III, in which REL-1017 was administered for 20 days to 232 subjects. The study did not achieve the primary endpoint of a statistically significant improvement in depression symptoms compared to placebo as measured by the Montgomery-Åsberg Depression Rating Scale, or MADRS, on day 28. In this study, the REL-1017 treatment arm showed a moderate reduction of 14.8 points on day 28 versus 13.9 points for the placebo arm. This was a higher than expected placebo response. Paradoxical results were observed in certain study sites where placebo dramatically outperformed REL-1017.
To better understand the paradoxical results, a post-hoc exploratory analysis using the band-pass method, which excludes sites with implausibly high or low placebo response, was conducted. In this study, an implausibly high or low placebo response was defined as a mean decrease from baseline in MADRS-10 score greater than 14 and less than three points. The results of the band-pass analysis showed a meaningful difference between REL-1017 and placebo greater than 4.9 points on the MADRS, representing a p-value <0.05 . It's important to note that while we are pleased with the statistically significant difference seen using the band-pass method, we understand that this is not sufficient to be used as an FDA submission, and we may consider planning additional studies.
I want to highlight that in RELIANCE III, REL-1017 demonstrated very favorable tolerability and safety, confirming the results of phase I and phase II studies, with no opioid-like effect, no withdrawal effect, and no psychotomimetic effect. While we are currently further evaluating the data from RELIANCE III, we believe that the primary driver behind the study not being successful was the enrollment of subjects who are not truly suffering from MDD and responded dramatically and rapidly to placebo. As an example of this, the top enrolling center had a mean change from baseline of 23 points in the placebo group.
As we approach the top-line readout for RELIANCE I, expected before year-end, it is important to note that the higher volume centers in RELIANCE III also recruited significantly in RELIANCE I. Mitigating that to some degree is the different patient population in RELIANCE I, that is patients that enrolled and should already been diagnosed with depression and are not responding adequately to at least one and up to three courses of antidepressant therapy. We cannot predict how these factors will balance out. Looking further ahead, we intend to apply several protocol and operational changes in the current enrolling RELIANCE II study and make certain improvement to how the trial is being conducted.
We now expect top-line results from this study next year. Once we have finalized and determined how to best execute on this enrollment, we will provide a firmer timeline for top-line result for RELIANCE II. Moreover, in order to be proactive and increase the likelihood of clinical success for REL-1017 as a potential therapy for MDD, an indication in which two successful studies are required to achieve FDA approval, we may consider initiating new clinical trials in 2023. As we apply key learnings from RELIANCE III to improve how RELIANCE II is being conducted going forward, we focus on the four key pillars that mainly impact the success of an MDD trial.
The protocol, the site selection, the patient selection, and the rating doctor. We will integrate our key learnings in this area into the RELIANCE II study and any possible additional study we may consider. Now let's move on to RELIANCE -OLS, the long-term open label safety study that is enrolling both rollover participants for all three pivotal studies as well as de novo participants. RELIANCE -OLS is ongoing and continues to enroll participants as planned. Data from this long-term open label safety study, which we now expect in first -half of 2023, will be part of the planned NDA filing package.
Finally, I want to emphasize that RELIANCE III was a trial execution fail, and we remain highly confident in the potential REL-1017 to be a safe and effective new therapy for this treatment of MDD. It is important to note that we have the financial flexibility to continue advancing REL-1017 in the clinic due to our strong balance sheet. Maged will review our financials in detail shortly, but we ended the third quarter with cash equivalents, and short-term investments of approximately $124 million. With that, I will now turn the call over to Maged for the review of the financials. Maged, the stage is yours.
Sure. Thank you, Sergio. Today, we issued a press release announcing our business and financial results for the three and nine months ended September 30, 2022, which I will now review. For the third quarter ended September 30, 2022, total research and development expense was approximately $30.5 million as compared to $34 million for the comparable period of 2021. The decrease was primarily related to a decrease in stock-based compensation. This non-cash charge totaled $3.2 million in the most recently completed third quarter. Total general and administrative expense for the third quarter ended September 30, 2022, was approximately $8.2 million, as compared to $8.7 million for the comparable period of 2021, a decrease of approximately $500,000 .
The decrease was primarily driven by a decrease in stock-based compensation. This non-cash charge totaled $5.2 million in the most recently completed third quarter. For the third quarter ended September 30, 2022, the net loss was $39.4 million, or $1.31 per basic and diluted share, compared to a net loss of $42.6 million or $2.44 per basic and diluted share in the comparable period of 2021. Turning to the results for the nine months ended September 30, 2022. Total research and development expense was approximately $86.5 million as compared to $65.3 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.
For the nine months ended September 30, 2022, total general and administrative expense was approximately $36.1 million as compared to $26.2 million for the comparable period of 2021. The increase was primarily driven by an increase in stock-based compensation. For the nine months ended September 30, 2022, the net loss was approximately $119.1 million or $4.04 per basic and diluted share, compared to a net loss of $91.4 million or $5.36 per basic and diluted share in the comparable period of 2021.
As of September 30, 2022, we had cash equivalents, and short-term investments of approximately $184.2 million, compared to cash equivalents, and short-term investments of approximately $211.9 million at December 31, 2021. As Sergio mentioned, our current cash position provides us with ample runway, or approximately two years of cash. I will now turn over the call to Sergio. Sergio?
Thank you, Maged. Before we take your questions, I would like to share that we have on the call with us today the RELIANCE program principal investigator, Dr. Maurizio Fava, the Chairman of the Harvard Medical School Department of Psychiatry, that can answer questions regarding the REL-1017 clinical development. Thank you, Maurizio, for joining us.
My pleasure.
With that, I will ask the operator to open the call for questions. Operator?
Thank you. At this time, I would like to remind everyone in order to ask a question, please press the star, then the number one on your telephone keypad. We'll pause for just a moment to compile the Q&A roster. First, we will go to Marc Goodman of SVB Securities.
Yeah. Thanks for taking my question. This is really on line for Marc. On RELIANCE i data you expected in first quarter, wondering, are you making any changes to this study? What are your current plans to do with the study sites where placebo outperformed the drug, and did you talk with FDA to get agreement for your data analysis? Thanks.
Yeah. Thank you for your question. Well, the RELIANCE I, it's pretty much done. We are planning to close the database in the next two, three weeks. We're, you know, we expect to have data before the end of the year, it's way too late to make any change. Now, I noticed in the opening remark there are, you know, there is some difference. The two factors in RELIANCE I that could make a difference. One is that the patient population is different. These are patients not naive, not monotherapy. They are patients have been supposed to be diagnosed with depression. They have been taking at least one treatment for at least six weeks, and they have not responded adequately.
Theoretically, Maurizio Fava can help us out on this topic, but theoretically these patients will respond less to placebo. On the other side, the sites and, you know, the operational issues that affected RELIANCE III are present, especially the sites that enroll large parts of the patients in RELIANCE III are also enrolled in RELIANCE I. We don't know how these two factors, one is in favor, the other one may not be in favor, how they will balance themselves. It's way too late to make any change. We want to see what the result will look like. Sorry, can you repeat the second part of your question?
Yeah, just wondering, what's your current plan for data analysis? It's gonna be the same for like RELIANCE III?
Yes. Yes, the same. We probably provide the band-pass, but, you know, the band-pass is a very good diagnostic tool, and it tells you if the product works or not. You know, we think that the primary analysis will be the same as RELIANCE III with all comers.
Got it. That's very helpful. Thank you.
Thank you.
Next, we'll take our question from Uy Ear of Mizuho.
Hi, guys. Thanks for taking my question. Just wanted to get a better understanding of the, I guess, the diagnostics or the tools that was used to assess the incoming patients in RELIANCE III, whether the tool captures patients who are, you know, have been chronically depressed or, you know, are episodically depressed. They've not really established sort of like a persistent state of depression. That's my first question. I guess my second question is, in RELIANCE I , I think you said the study is stopped and could you tell us whether you enrolled the expected number of patients and whether the DSMB has asked you to stop the enrollment or is it, you think it's sufficiently powered? Just wanted to get a better sense of what's going on there. Thanks.
Sure. Sure. Thanks for the question. Dr. Fava.
Sure.
You may take the first one. You help us out a lot to analyze this data, so please go ahead.
Sure.
I will then answer the second question.
Sure.
Please go ahead.
It's a great question. I'm Maurizio Fava, the Chief of Psychiatry at Massachusetts General Hospital and the Principal Investigator for the studies. In, you know, one of the characteristics of the monotherapy trial was that patients had to be off medicines, so they had to be typically treatment naive, never treated during the current episode. In addition, they had to be relatively lean for U.S. standards. That is, they had to have a BMI between 18 and 30. We know, for example, that chronic and recurrent depression is associated with weight gain, so that people end up having BMIs well in their 30s.
I think that the combination of the pandemic causing stress-induced depressive episodes in individuals who do not have a prior history of depression has led to a number of individuals seeking treatment from a study because they were, you know, having trouble accessing treatment because they were not in treatment, if you wish, before. You know, as we see often in stress-induced depressive episodes, have a high probability of spontaneous remissions. They get better on their own. If they get better on their own, they can get better on placebo as well. In the 301 study, we have patients who have to be on antidepressants, have to have failed to respond to antidepressants.
They have to be in treatment with a psychiatrist. They're very likely to have recurrent forms of depression. More bona fide conditions, medical conditions. You know, the challenge is that according to our DSM-V classification, a person who develops depressive symptoms acutely meets the exact criteria for a major depressive episode, exactly as someone who has had recurrent episode or has chronic symptoms. When we designed the monotherapy study, we did not factor in the impact of the pandemic on kind of the diagnosis of depression in the general population.
You know, I can tell you, as the Chief of Psychiatry at Mass General, we've seen a tripling of the referrals for anxiety and depression to our department. We've seen nationally in epidemiological studies that we've seen a tripling of anxiety and depression. Are these diseases where we're seeing this rise of people experiencing depression? Are these, you know, stress-related, you know, depressive episodes that in some ways will spontaneously resolve? The answer, you know, we don't know the answer, but it clearly affected our monotherapy trial. In my opinion, this should not be the issue in patients who have been, you know, under treatment with a psychiatrist, not responding to treatment.
The chances of spontaneous remissions are very, very small in that population compared to patients never treated, first episode, you know, caused by the pandemic. Sergio?
Thank you, Dr. Fava. I hope that answered your question. The second part of the question is the number of patients. The number of patients was a variable up to 350 patients, 360. The DSMB recommended to stop the trial at the minimum number. It was 220. We exceeded a little bit that, and we are exceeding a little bit that. But don't read anything into that because the data monitoring committee may have made a recommendation for two reasons. The trial is futile, so it is not worth to proceed and add more patients, that it would never be statistically significant, or the trial is already statistically significant at the 220 number.
I mean, what the DSMB recommended, it doesn't mean anything in terms of results. No, no way to read if it's because the trial will be successful or the trial will not be successful.
Okay.
Hope that answers also the second part of your question.
Yeah. Thank you very much. Thanks.
Next we go to Yatin Suneja of Guggenheim Partners.
Hey, guys. Just a couple questions from me just to clarify. How many of the sites that were in the monotherapy study are going to be overlapping in RELIANCE I? I think previously when we had discussions with you seemed to imply that there is a possibility of increasing the sample size. I mean, if the study is still not done yet, why not increase the size in order to be statistically significant?
Yeah. Well, thank you, Yatin. Yeah. Good, good question. In terms of overlapping of sites, I don't have the exact number, but there is like I would say that overlapping is pretty high between monotherapy and RELIANCE I. The one that really matters is the sites that have a high, they enroll a lot of patients, the high enrolling sites, and they are the ones that have this paradoxical response where placebo outperformed the drug by quite a bit, and it's kind of isolated to a few sites. So these are the ones that really could make the difference. We don't know.
The sites are in RELIANCE I as well, but we don't know if the phenomenon is going to be the same or not. As Dr. Fava was saying, this is different patient populations. These sites may have, you know, different results, but we won't know it until we see it. We discussed about expanding the enrollment in RELIANCE RELIANCE I with the DSMB recommendation. If the site or if the trial is somewhat compromised, adding more patients will just, you know, expand time, cost, and probably unless we triple or double the number of patients won't make it such a big difference.
It's much more productive to just see how the results look like, learn from the results and eventually likely start, you know, new at least one new trial and from scratch, applying all what we have learned from the monotherapy and what we will learn from the RELIANCE I. The decision was really just let's see how the data look like as you know the profile of the patient is different.
Got it. To clarify, is the RELIANCE II already ongoing or that one is also on pause given that you first want to see what RELIANCE I is gonna yield?
Clearly, how RELIANCE I will look like it will have an impact on RELIANCE II. For now, we are just implementing quite a bit of changes from the protocol to limiting the number of patients per site. In changing the way, you know, the rating is done from a localized to most likely a lot less localized rating. We are implementing these changes but, you know, technically the trial is open. They only enroll 25% of roughly of the, you know, the full patient population. RELIANCE II is still a very valuable trial.
The site and, you know, the similarity with RELIANCE I and III, the sites that they affect in RELIANCE III, they're not in RELIANCE II. That's already an indication, the number of patients low. We don't think it's a compromised study. That will, you know, continue to enroll and we expect to complete and have data sometime next year probably. I hope I answered your question.
We'll move to our next caller, and that will be Andrea Tan at Goldman Sachs.
Hi, Sergio. Thanks for taking my question. Maybe one.
Andrea.
Hi. Maybe one follow-up there. Just wondering if you've been able to understand more what happened at those sites where you did observe the paradoxical results. Anything in particular that they may have been doing differently on study execution than the other sites? Do you think additional training is maybe necessary as you look to these improvements that you were speaking about for RELIANCE II?
Yeah. I will let Maurizio Fava to answer that question. From my perspective, clearly additional training is needed for these sites and then, you know, it has some enrollment. These sites are sites that, as you know, we call them commercial sites, but they enroll patients as a basis of their business so they are not hospitals or clinics or so they're pure like the sites that enroll patients for clinical trial. Pretty much all the patients that they enroll there have been enrolled coming from social media advertising. I mean, you know, when you enroll a lot of patients, you enroll fast and, you know, sometimes the diagnosis is done a little bit on the fast side.
I let Maurizio Fava, he's really the expert of this, to go into more detail. Maurizio.
Yeah. No, it's a great question. I think that, you know, I'm not certain necessarily that the fault was in the assessment. Again, we need to consider the population that we were trying to enroll. The study specifically looked for people untreated with major acute depressive episodes in the midst of a pandemic and recruited primarily through advertisement. If, you know, if I'm already an existing patient, I have my doctor. If I have a recurrence of my depression, I go to my doctor, I go back to the medicines I tried before. If I've never been treated before, I may respond to an ad. I may, you know, look at a study.
Whenever you're doing a study that's, you know, specifically looks for people who have never been treated before, who have developed symptoms acutely, don't have chronic or recurrent depression, and therefore you don't know that, you know, at least in prior episodes have shown, you know, that they've responded only to medicines. You're likely to have what we call abnormal placebo responses. Abnormal placebo responses are due to spontaneous remissions that may have happened, you know, at any point during the study. The same sites that may have performed terribly by enrolling these people who had depression but not recurrent. Remember, we did not ask for chronic or recurrent depression.
We asked for acute depression in untreated patients who are not treated by anybody. You're looking for the best case scenario of someone who in some ways is very likely to respond to the first therapeutic intervention that they receive. You know, just interacting with people, getting out of the house during the pandemic, et cetera. Whereas in the other study, we're taking people who are in treatment, who are currently engaged, who are likely to have either chronic or recurrent depression. It's like a different disease altogether.
I don't know if I would predict that the same sites that perform badly on the monotherapy trial are gonna also perform badly on the augmentation study because it's two different populations and the referral process is very different. I don't know if that addresses your question, Andrea.
Yeah, that was really helpful. As a follow-up there, I guess, to what extent do you believe the SAFER interview should have been able to, you know, maybe mitigate some of those issues or caught people that, you know, maybe were not appropriately enrolled in the trial? Or is that just the nature of the different patient populations that you're referring to that you really can't rely on the SAFER interview?
Yeah. I think that.
Dr. Fava . [It’s for you]?
I'm pretty confident that, you know, the SAFER would clearly protect you from high placebo response rates in patients who are currently treated. In patients who are untreated, you know, normally, a SAFER interview determines what medicines you're on. Is the treatment adequate? What's the treatment history? How many times have you been diagnosed? Et cetera, et cetera. So the interview gives a sense of the course of illness and the confidence that you're dealing with a patient with a real disease. In a monotherapy trial of an acute episode, there's no question about treatment because there's no treatment history. There's no question about course of illness because there's no requirement of chronic or recurrent.
Therefore you're in a situation of high stress like you know, like the pandemic, COVID-19. You know, even an independent interview is not going to protect you against the spontaneous remissions. I think that it's really the nature of the population that is very hard. You know, had those patients with spontaneous remissions had been assigned to active treatment, right, instead of the placebo in those sites where they outperformed, you know, the placebo outperformed the drug, the drug would have looked fantastic. You know, you often hope the randomization takes care of it. But at the level of a given site, you don't know if you know, a randomization will protect you against these spontaneous remissions.
The odds of spontaneous remissions are far greater in a monotherapy trial where you're recruiting only acute depressive episodes.
Got it. Okay. Maybe one last question, if I could squeeze it in for you, Sergio. Just wondering if you could provide more color on the additional studies that you mentioned that you're thinking of conducting. Would this be for monotherapy specifically, or is this, I guess, maybe under the condition that RELIANCE I is maybe not successful, and you would have to do a second, phase III trial for adjunctive? Thanks so much.
Yeah. No, thank you, Andrea. Look, as much as I wish, we really need— we want to see RELIANCE I data result before we make any decisions because moving forward, we'll probably continue to go into the treatment of patients that did not respond adequately to a treatment. You know, the RELIANCE I data are very important, critical to understand how we will move forward. The FDA, we believe they will want positive phase III data. You know, we will planning accordingly. Because in depression, it's not unusual to have failed study. I mean, J&J had, I believe, three out of five failed studies, and the first two Prozac studies failed.
I mean, it hurts when it affect directly, but is not very unusual. We will really base the plan based on the first adjunctive trial results. We are planning to start at least one more trial. We will be a lot more precise in January after we see the 301 data, we believe, in December. Sorry for that, but we'll give you all the information as soon as we have more accurate plans to how to move forward.
Great. Thanks, everyone.
Thanks, Andrea.
Now we will move to Andrew Tsai, Jefferies.
Hi. Thanks, and good afternoon. Thanks for the questions. That's unfortunate to see RELIANCE III, but hopefully things get better from here. First question is, for RELIANCE III, the outlier sites, what percentage of all patients enrolled in RELIANCE III did these outlier sites enroll? And then what percent of patients in those outlier sites, I guess, do you think will be enrolled in RELIANCE I and RELIANCE II respectively?
Yeah. Thanks, Andrew, for the question. It's a little bit difficult to answer precisely, but like, the roughly the sites that had results that we defined paradoxical, where the placebo outperformed the drug for whatever reason, and they enroll about between 25% and 30% of the patients in RELIANCE III in the monotherapy. In the first adjunctive, now it's unfair to make a comparison with the same sites because as Dr. Fava said, the patient population is different. These sites, clearly they enrolled between 30%-40% of the patients, but the patient population is different and we don't know how these sites really perform the diagnosis of the patients and, you know, it may be different.
We hope it's gonna be different from monotherapy. In terms of like, percent of patients was between 25%-30% in monotherapy, and it's going to be between, I would say mid -30s, in maybe a little bit more than that in the first RELIANCE I, the first adjunctive trial. None of these sites is in RELIANCE II.
Okay. None of the sites. Okay. I guess, maybe a bigger picture question is, you know, is this such situation of paradoxical results, is it a common occurrence in failed depression studies, or is this kind of an exception due to COVID? Just curious what your bigger picture thought is.
Yeah. Dr. Fava, is it? Can you help me out on this? You're really expert.
If you look at approved antidepressants, you know, all the meta-analysis have shown that about 40% of the trials were positive. The 60% of those studies that were positive, typically, what contributed to the lack of signal detection was an average placebo response that was excessive. An analysis by Dr. Papakostas show that when you have placebo response rates above 40%, you tend to lose the ability to detect the signal. However, the challenge for monotherapy trials is right now the current stressful situation, the economy, the pandemic situation, so forth, because it will inflate the rates of depression in general population.
If you are simply looking at an acute major depressive episode, those patients that have a response to the stress do meet criteria. Unless you specify that you want chronic and recurrent depression in monotherapy, unless you specify it, and we did not do that, you're more likely to have this what we call atypical spontaneous remissions because of the situation we're in. I, you know, I apologize, Sergio, but I have another call at 5:15 P.M., so I only have three minutes left.
Thank you, Maurizio. Highly appreciated.
One last one is just the cadence of the event. Sounds like RELIANCE I reads out December. Would you then meet with the FDA to kind of discuss whether you can make certain improvements to RELIANCE II following RELIANCE I, depending on whatever outcome it shows, and then you get back to the street? What would be those certain improvements?
Yeah. I think, thanks, Andrew. At this point, first of all, we really want to see the RELIANCE I result. At this point, we don't think there is really any need to meet with the FDA because the changes planned that we are actually implementing in RELIANCE II and most likely in any other trial that if we will do more additional trial in the future, they are not FDA dependent. It's really purely operational. Like maybe I can give you some example. There is a few of them, but you know, they're limiting the number of patients enrolled per site.
Like, you know, when a site enrolls four patients and do an audit and see how things are going to be sure that, you know, the sites, you know, perform at the maximum level. You know, we probably are making some change in the ratings and the decentralized rating may add maybe too much variability and we may centralize more the rating. We are simplifying the protocol of RELIANCE II and any other potential trial.
Reason being that we now have a very large amount of treated patients and safety data, so there is no need to add ECGs and so the protocol will be more simple, so it will be also easier for the site to enroll patients. Now we can go on all these, but these are all operational, non-FDA related changes.
Sergio
Nothing has attached.
Sergio, if 301 is positive, then we won't necessarily have to make major operational changes to 302.
Right.
Okay. Just one last clarifying is, none of the outlier sites are in RELIANCE II? Is that what I heard you say earlier?
Correct.
Okay.
All right.
Thank you.
Yeah, one comment I would make. I would not really focus and compare them on different sites. It's more the current situation. We'll see how RELIANCE I looks like, but it could be that these sites could have performed very well in RELIANCE I. It's more like the complexity of the old and the diagnosis and you know the kind of patients involved that made most of the difference. I would not say that these are not good sites. These are very reputable, large sites. It is not the first depression trial they have done. They've done many of them and you know they're highly qualified.
I would say it's more, you know, the kind of patients for the monotherapy trial that was mainly responsible. Clearly, if these sites would have been limited to a single-digit patient and not to 20+, the impact would have been lower. Again, we'll see what 301 looks like before we make, you know, major amendment.
Very clear. Okay. Thank you.
Now we will go to Jay Olson of Oppenheimer.
Hey, Jay.
Oh, hey. Thanks for taking the questions. Can you just talk about what the path forward now is to pursue, monotherapy MDD indication for REL-1017?
Yeah, thanks for the question, Jay. Look, it is an artificial and if Dr. Fava is still on the call, may help on this, but it is really an artificial, self-created difference between adjunctive. You have seen one of the competitors that we got approval for treatment of MDD, is a combination of two different antidepressants. The indication that we are pursuing is treatment of patients affected with major depression that have not responded adequately to the current, you know, treatment they are on. Then the doctor will decide if it's going to be an add-on or it will stop the non-performing antidepressant and replace with REL-1017. We are looking for broader label.
You know, the trial will be done in patients that have been failing with the current treatment, also because the diagnosis is a lot more precise and there is a lot more confidence these patients are really affected by major depression and not by personality disorder, anxiety or other similar depression that can be confused with major depression. If we are successful, it's going to be like a broader label, treatment of depression.
Okay. Thank you. That's helpful. Is there any color you could provide around what percent of patients in the RELIANCE studies have opted into the open-label extension?
In the monotherapy. That's a good way. You know, I don't have that number off the top of my head. Maged is the number.
Yeah.
You know.
They broadly, the numbers that we have is about 75% of patients have opted into, you know, going into the open label study.
That's for all the files, though, not specifically to the monotherapy.
Okay, great. Thank you. That's helpful. Thanks for taking the question.
I think we have around 600 patients in the long-term safety now, so.
Yep.
Okay. Super helpful. Thank you.
Thank you, Jay.
Now we will go to Joon Lee of Truist Securities.
Hi. Thanks for taking my questions. Do you have any data comparing the PK/PD of powder formulation to tablet formulation from others? Well, REL-1017.
Thank you, Joon. We will, but I believe Paolo Manfredi and the team, they look at the PK profile. There is no difference.
The PK profile of the powder and the tablet. Gotcha.
Yeah. Well, we have the powder in solution from the phase II data and we look at the profile in monotherapy and the blood levels, there is no difference.
Okay. In the press release, you say that you now expect these results in 2023. Is that referring to RELIANCE II? If so, wasn't that always the case, that you kind of expect that in 2022–2023?
Well, yeah, we don't, you know, at this point, try not to be too specific on if it is first half, second half. Consider that RELIANCE II is about 25% enrolled, but also that the focus was really on monotherapy. We put a lot of effort, a lot of advertising and a lot of energy in completing monotherapy. And then RELIANCE I. RELIANCE II has always been not slowed down, but not pushed to enroll fast because we wanted to see how the other two go. Now in 2023, RELIANCE II will be the focus. Eventually with maybe another phase III similar study that, you know, we'll decide after the 301 results.
We expect we should be able to complete it within 2023. After RELIANCE I data in December, we'll be a lot more specific on what the plan will be.
Right. Thank you so much.
Thank you, Joon.
I think that does conclude today's question and answer session. I would like to turn things back to Sergio for any closing comments.
Thank you all, and thank you, Dr. Fava. Thank you to the team. In closing, I really remain grateful to the Relmada team for the continued hard work and dedication to executing what that for us is really a mission. I would also like to extend sincere thanks to the participants and the clinical partners involved in the REL-1017 trial for the effort in advancing this important product candidate through the clinic. We look forward to 301 data and continue to the clinical development of REL-1017 and hopefully get it approved at some point. Thank you very much and enjoy the rest of the day.
With that does conclude today's conference call. We'd like to thank you again for your participation. You may now disconnect.