Earnings Call Transcript - RLMD Q3 2022

Operator, Operator

Good afternoon. My name is Kathy, and I'll be your conference operator for today. I would like to welcome everyone to the Relmada Therapeutics, Inc. Third Quarter 2022 Earnings Call. All lines have been muted to avoid background noise. After the speakers' remarks, there will be a question-and-answer session. Brian Ritchie, you may begin your conference.

Brian Ritchie, Moderator

Thank you, operator, and thank you all for joining us this afternoon. With me on today's call are Chief Executive Officer, Sergio Traversa; and Chief Financial Officer, Maged Shenouda. This afternoon, Relmada issued a news release providing a business update announcing financial results for the three and nine months ended September 30th, 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 ended December 31, 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 10, 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?

Sergio Traversa, CEO

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 comments, Maged Shenouda, our Chief Financial Officer, will review our financial results and balance sheet, and we will then take your questions. As a reminder, RELIANCE I and RELIANCE II are two ongoing Phase 3 sister two-arm, placebo-controlled, pivotal studies evaluating REL-1017 25 milligrams as a potential adjunctive treatment for MDD. RELIANCE III was the Phase 3 2-arm, placebo-controlled, registrational study evaluating REL-1017 25 milligrams as a potential monotherapy treatment for MDD. We announced topline results last month for RELIANCE III in which REL-1017 was administered for 28 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-Asberg Depression Rating Scale or MADRS, on day 28. In this study, the REL-1017 treatment arm showed a MADRS reduction of 14.8 points at 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 result, a post-op exploratory analysis using the bandpass method, which excludes sites with unplausibly high or low placebo responses, was conducted. In this study, an unplausibly high or low placebo response was defined as the mean decrease from baseline in MADRS 10 score greater than 14 and less than 3 points. The results of the bandpass analysis showed a meaningful difference between REL-1017 and placebo, greater than 12.9 points on the MADRS, representing a p-value below 0.05. It's important to note that while we are pleased with the statistically significant difference seen using the bandpass 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 1 and Phase 2 studies with no opioid-like effect, no withdrawal effect, and no psychotomimetic effect. While we are currently further evaluating the detail 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 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 topline readout for RELIANCE I expected before year-end, it is important to note that the higher enrolling centers in RELIANCE III also recruited significantly in RELIANCE I. Mitigating that to some degree is the different patient population RELIANCE I, that is patients that enrolled should already have 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 up. Looking further ahead, we intend to apply several plausible and operational changes in the current enrolling RELIANCE II study and make certain improvements to how the trial is being conducted. We now expect topline 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 topline results 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 will 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 process. We will integrate our key learnings in these areas 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 from all three pivotal studies as well as de novo participants. RELIANCE-OLS is ongoing and continues to involve participants as planned. Data from this long-term open-label safety study, which we now expect in the 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 phase, and we remain highly confident in the potential REL-1017 to be a safe and effective new therapy for the 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, cash equivalents and short-term investments of approximately $124 million. With that, I will now turn the call over to Maged for a review of the financials. Maged, the stage is yours.

Maged Shenouda, CFO

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 $0.5 million. 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, cash equivalents, and short-term investments of approximately $184.2 million compared to cash, 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 the call to Sergio.

Sergio Traversa, CEO

Thank you, Maged. Before taking 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 Harvard Psychiatry Department, who can answer questions regarding the REL-1017 clinical development. Thank you, Maurizio, for joining us.

Maurizio Fava, Principal Investigator

My pleasure.

Sergio Traversa, CEO

With that, I will ask the operator to open the call for questions. Operator?

Operator, Operator

Thank you. And first, we will go to Marc Goodman of SVB Securities.

Guofang Li, Analyst

Hey, thanks for taking my question. This is Rudy on the line for Marc. So on RELIANCE I that you expected in the first quarter, I'm wondering, are you making any changes to this study? What are your current plans to deal with the study size where placebo outperformed the drug? And did you consult the FDA to get an agreement for your data analysis?

Sergio Traversa, CEO

Thank you for your question. Well, RELIANCE I is pretty much done. We are planning to close the database in the next two to three weeks, so we expect to have data before the end of the year. So it's way too late to make any changes. And now I noted in the opening remarks, there are some differences. The two factors in RELIANCE I that could make a difference: One is that the patient population is different. These are patients not naïve, not monotherapy. They're patients that have been supposed to be diagnosed with depression. They have been taking at least one treatment for at least six weeks and are not responding adequately. And theoretically, as Dr. Fava can help us with this topic, but theoretically, these patients would respond less to placebo. On the other side, the sites and the operational issues that affected RELIANCE III are present, especially the sites that enrolled a large part of the patient in RELIANCE III who also enrolled in RELIANCE I. We don't know how these two factors, one was in its favor, and the other one may not be in favor, will balance themselves. But it's way too late to make any changes. We want to see what the results will look like. And sorry, can you repeat the second part of your question?

Guofang Li, Analyst

Yes. Just wondering what's your current plan for data analysis? Is it going to be the same as RELIANCE III?

Sergio Traversa, CEO

Yes, the same. We will probably provide bandpass, but the bandpass is a very good diagnostic tool, and it tells you if the product works or not. But we think that the primary analysis will be the same as RELIANCE III with all comers.

Guofang Li, Analyst

Got it. That’s very helpful. Thank you.

Sergio Traversa, CEO

Thank you.

Operator, Operator

And next, we'll take our question from Uy Ear of Mizuho.

Uy Ear, Analyst

Hi, guys. Thanks for taking my question. Just wanted to get a better understanding of the diagnostics or the tools that were used to assess the incoming patients in RELIANCE III, whether the tool captures some patients who have been chronically depressed or are episodically depressed? They’ve not really established a persistent state of depression. So that's my first question. And I guess my second question is in RELIANCE I, I think you said the study is stopped. Could you tell us whether you enrolled the expected number of patients and whether the DSMB has asked you to stop enrollment? Or do you think it's sufficiently powered? Just wanted to get a better sense of what's going on there. Thanks.

Sergio Traversa, CEO

Sure. Thanks for the important question. Dr. Fava, you may take the first one, helping us understand how to analyze this data. Please go ahead. I will then answer the second question. Please go ahead.

Maurizio Fava, Principal Investigator

Sure. It's a great question. I'm Maurizio Fava, the Chief of Psychiatry at Mass General and the principal investigator for the studies. One of the characteristics of the monotherapy trial was that patients had to be off medicines. So they had to be typically treatment-naïve, never treated during the current episode. In addition, they had to be relatively lean for U.S. standards, that is they have to have a BMI between 18 and 30. We know, for example, that chronic and recurrent depression is associated with weight gain. People end up having BMIs well in the 30s. So I think that the combination of the pandemic causing stress-induced depressive episodes in individuals who did not have a prior history of depression has led to a number of individuals seeking treatment from a study because they were having trouble accessing treatment because they were not in treatment, if you wish, before. And as we see often, stress-induced and depressive episodes have a high probability of spontaneous remissions. They get better on their own. But if they get better on their own, they 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. And so they are very likely to have recurrent forms of depression, so more bona fide conditions, medical conditions. The challenge is that according to our DSM-5 classification, the person who develops depressive symptoms acutely meets the criteria exactly for a major depressive episode exactly as someone who has had recurrent episode or has chronic symptoms. So when we designed the monotherapy study, we did not factor in the impact of the pandemic on the diagnosis of depression in the general population. I can tell you as the Chief of Psychiatry in Mass General, we've seen a tripling of the referrals for anxiety depression to our department. And we've seen nationally in the epidemiological studies that we've observed a tripling of anxiety and depression. So are these diseases what we're seeing is a rise of people experiencing depression? Or are these stress-related depressive episodes that will continue to resolve? The answer we don't know, but it clearly affected our monotherapy trial. In my opinion, this should not be the issue in patients who have been under treatment with a psychiatrist not responding to treatment. The chances of spontaneous remissions are very small in that population compared to patients never treated first step caused by the pandemic.

Sergio Traversa, CEO

Thank you, Maurizio. I hope that answers your question. Regarding the second part of your question on the number of patients, we had a variable target of up to 350 or 360 patients. The Data Safety Monitoring Board recommended stopping the trial at the minimum of 220 patients, and we exceeded that slightly. However, it's important not to read too much into this recommendation. The committee may have had two reasons: either that the trial is futile and adding more patients wouldn’t yield statistically significant results, or that the trial has already reached statistical significance with just 220 patients. Therefore, the recommendation from the DSMB doesn't provide insight into whether the trial will ultimately be successful or not. I hope that addresses the second part of your question.

Uy Ear, Analyst

Yes. Thank you very much. Thanks.

Sergio Traversa, CEO

Thank you.

Operator, Operator

And next, we go to Yatin Suneja of Guggenheim Partners.

Yatin Suneja, Analyst

Hey, everyone. I have a couple of questions for clarification. What percentage of the sites from the monotherapy study will also be included in RELIANCE I? In our earlier discussions, you suggested that there might be a chance to increase the sample size. If the study isn't finished yet, why not expand the size to ensure it's statistically significant?

Sergio Traversa, CEO

Yes, thank you, Yatin. I understand your question. I don't have the exact number of site overlaps, but there is a significant overlap between the monotherapy study and RELIANCE I. The key sites that enrolled a substantial number of patients are the ones where the placebo outperformed the drug to a considerable extent, and this issue is limited to a few locations. These sites could potentially have a major impact. While these sites are also included in RELIANCE I, we are uncertain if the same phenomenon will occur there. As Dr. Fava mentioned, this is a different patient group, so the results from these sites could vary, but we won't know until we analyze the data. We also talked about the option of expanding enrollment in RELIANCE I based on the DSMB's guidance. If the trial is somewhat compromised, adding additional patients would only extend the duration and increase costs, and unless we significantly increased the patient count, it likely wouldn't change the outcome meaningfully. Therefore, it's more efficient to evaluate the results as they come in, learn from them, and eventually, we can initiate new trials based on the knowledge gained from both the monotherapy and RELIANCE I. The decision was essentially to wait and see how the data turns out, given that the patient profiles are different.

Yatin Suneja, Analyst

Got it. And then to clarify, is RELIANCE II already ongoing? Or is that also on pause given that you first want to see what RELIANCE I is going to yield?

Sergio Traversa, CEO

Well, clearly, RELIANCE I will have an impact on RELIANCE II. For now, we are implementing quite a few changes from the protocol to limiting the number of patients per site. So we are changing how the rating is done from a localized to a lot less localized rating. So we are implementing these changes, but technically, the trial is open. We’ve only enrolled about 25% roughly of the full patient population. So RELIANCE II is still a very valuable trial. The sites are not similar to RELIANCE I and III, the sites that affected RELIANCE III are not in RELIANCE II. And so that’s already an indication the number of patients is low. So that's a perfectly non-compromised study that will continue to enroll, and we expect to complete and have data sometime next year, probably. I hope I answered your question.

Operator, Operator

And we'll move to our next caller, and that will be Andrea Tan of Goldman Sachs.

Andrea Tan, Analyst

Hey, Sergio, thanks for taking my question.

Sergio Traversa, CEO

Hi, Andrea.

Andrea Tan, Analyst

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? And do you think additional training is maybe necessary as you look to the improvements that you were speaking about for RELIANCE II?

Sergio Traversa, CEO

Yes. I will let Dr. Fava to answer that question. From my perspective, clearly additional training is needed for these sites and then faster enrollment. These sites are sites that we call commercial sites, but they enroll patients as a base of their business, so they are not hospitals or clinics. So they are pure like the size of enrolled patients for clinical trials. And pretty much all the patients that they enrolled have been enrolled coming from social media advertising. So when you enroll a lot of patients, you enroll fast. And sometimes the diagnosis is done a little bit on the cost side. But I'll let Dr. Fava, he's really the expert on this, cover more in detail. Maurizio?

Maurizio Fava, Principal Investigator

Yes, that's a great question. I'm not entirely sure that the assessment was at fault. We need to consider the population we aimed to enroll. The study specifically targeted individuals who had not been treated for major acute depressive episodes during a pandemic and primarily recruited through advertisements. If I'm already a patient with a recurrence of depression, I would consult my doctor and return to previously tried medications. However, if I have never received treatment, I might respond to an ad or be interested in a study. In studies that seek individuals who have never been treated before and are experiencing acute symptoms, we often observe abnormal placebo responses. These responses may arise from spontaneous remissions occurring during the study. The same site that may have struggled by enrolling individuals with depression, who do not have recurrent symptoms, focused on acute depression in patients who have not been treated. Thus, they were looking for individuals who are likely to respond positively to their first therapy, particularly those engaging socially during the pandemic. In contrast, the other study involved patients already undergoing treatment, likely with chronic or recurrent depression. This makes it almost like a different disease. Therefore, I can't say with certainty that the same sites that performed poorly in the monotherapy trial will also do poorly in the augmentation study, as we are dealing with two distinct populations and the referral processes differ significantly. I hope that answers your question, Andrea.

Andrea Tan, Analyst

Yes. 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 mitigate some of those issues or caught people that may not have been 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?

Maurizio Fava, Principal Investigator

Yes, I think that.

Sergio Traversa, CEO

Dr. Fava, this is really for you.

Maurizio Fava, Principal Investigator

I'm pretty confident that the SAFER would clearly protect you from high placebo response rates in patients who are currently treated. In patients who are untreated, normally, a SAFER interview determines what medicines you're on, how adequate is the treatment? 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 with acute episodes, there’s no question about treatment because there's no treatment history. There's no question about the course of illness because there's no requirement for chronic or recurrent. And therefore, you're in a situation of high stress like the pandemic. Even an independent interview is not going to protect you against spontaneous remissions. So I think that it's really the nature of the population that is very hard. And had those patients with spontaneous remissions been assigned to active treatment instead of the placebo at those sites where they outperformed the drug, the drug would have looked fantastic. So you often hope the randomization takes care of it. But at a given site, you don't know if randomization will protect you against these spontaneous remissions. But the odds of those spontaneous remissions are far greater in a monotherapy trial where you're recruiting only acute depressive episodes.

Andrea Tan, Analyst

Got it. Okay. And then 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 you’re thinking of conducting. Would this be for monotherapy specifically? Or is this maybe under the condition that RELIANCE I is not successful and you would have to conduct a second Phase III trial for adjunctive?

Sergio Traversa, CEO

Yes, thank you, Andrea. We really need to see the RELIANCE I data results before making any decisions. Moving forward, we'll likely continue treating patients who did not respond adequately to their current treatment. The RELIANCE I data is crucial for understanding our next steps. We believe the FDA will require two positive Phase III data, so we will plan accordingly. In depression, it's not uncommon to have failed studies; I believe there were three out of five failed studies, and the first two Prozac studies also failed. While it hurts when this has a direct impact, it's not unusual. We will base our plan on the results of the first adjunctive trial and are planning to start at least one more trial. However, we will have a clearer plan in January after reviewing the 301 data, which we expect in December. We will provide all relevant information as soon as we have a more defined approach for moving forward.

Andrea Tan, Analyst

Great. Thanks, everyone.

Sergio Traversa, CEO

Thanks, Andrea.

Operator, Operator

And now we will move to Andrew Tsai, Jefferies.

Andrew Tsai, Analyst

Hi, thanks and good afternoon. Thanks for the questions. It's unfortunate to see RELIANCE III, but hopefully, things get better from here. So 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?

Sergio Traversa, CEO

Yes. Thanks, Andrew, for the question. It's a little bit difficult to answer precisely. But roughly, the site that had results that we define as paradoxical, the placebo outperformed the drug for whatever reason, enrolled about between 25% and 30% of the patients in RELIANCE III in the monotherapy. In the first adjunctive, it's unfair to compare these sites because as Dr. Fava said, the patient population is different. Traditionally, they enrolled between 30% to 40% of the patients, but we hope the study will be different. We expect that we will likely have better data than in the monotherapy trial. But in terms of the percent of patients, it was between 25% and 30% in monotherapy, and it will be between, I would say, mid-30s, maybe a little more than that in the first adjunctive trial. None of these sites is in RELIANCE II.

Andrew Tsai, Analyst

Okay. None of the sites. Okay. And so I guess a bigger-picture question is, is this situation of paradoxical results 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.

Sergio Traversa, CEO

Dr. Fava, can you help me out with this? You are really the expert.

Maurizio Fava, Principal Investigator

Sure. When examining approved antidepressants, meta-analyses reveal that around 40% of them had positive trial results. The remaining 60%, which were also positive, contributed significantly to the challenge of detecting real efficacy due to a high average placebo response. Evidence shows that when placebo response rates exceed 40%, it becomes difficult to identify a genuine effect. The difficulty in monotherapy trials stems from the current challenging environment, including economic stress and the pandemic, which has led to increased depression rates in the general population. In cases of acute major depressive episodes, patients responding to stress can still meet clinical criteria. Without clearly defining the need for chronic and recurrent depression in monotherapy, it becomes more likely to observe spontaneous remissions due to the prevailing circumstances. I apologize for cutting this short, but I have another call at 5:15, so I have only a few minutes left.

Sergio Traversa, CEO

Thank you, Maurizio. Highly appreciate it.

Andrew Tsai, Analyst

And one last one is just the cadence of the event. It sounds like RELIANCE I reads out in 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? And would these certain improvements be?

Sergio Traversa, CEO

Yes, thanks, Andrew. At this time, we really want to see the results from RELIANCE I. However, we don't think there is a need to meet with the FDA because the changes we are planning to implement in RELIANCE II and likely in any future trials are not dependent on the FDA. These are purely operational changes. For example, we are limiting the number of patients enrolled per site. When a site enrolls four patients, we conduct an audit to assess how things are going and ensure optimal site performance. We will probably make some adjustments to the ratings, and the decentralized ratings may introduce too much variability, prompting us to centralize more of the rating process. There are quite a few changes, but all of them are operational and not related to the FDA. Nothing is finalized.

Maurizio Fava, Principal Investigator

And Sergio, if RELIANCE I is positive, then we won't necessarily have to make major operational changes to RELIANCE II.

Andrew Tsai, Analyst

Okay. And just one last clarification is none of the outlier sites are in RELIANCE II. Is that what I heard you say earlier?

Sergio Traversa, CEO

Correct. Correct.

Andrew Tsai, Analyst

Okay, all right. Thank you.

Sergio Traversa, CEO

But one comment I would make is that I would not really focus on categorized sites. It's more the current situation. And we'll see how RELIANCE I looks, but it could be that these sites could have performed very well in RELIANCE I. So it's more about the complexity of it all and the diagnosis and the kind of patients enrolled that make most of the difference. So I would not say that these are not good sites. These are very reputable large sites that it's not the first depression trial they've done. They have done many of them, and they are highly qualified. So I would say it's more the kind of patients for the monotherapy trial that were mainly responsible. Clearly, if these sites had been limited to a single-digit patient and not to 20 plus, the impact would have been lower. But again, we'll see what RELIANCE I looks like before making major amendments.

Andrew Tsai, Analyst

Very clear. Okay, thank you.

Operator, Operator

And now we will go to Jay Olson of Oppenheimer.

Jay Olson, Analyst

How are you? Great. Thanks for taking the question. Can you just talk about what the path forward now is to pursue monotherapy MDD indication for REL-1017?

Sergio Traversa, CEO

Yes. Thanks for the question, Jay. It is not official. And if Dr. Fava is still on the call, he may help on this, but it is really not official. We’re creating a difference between adjunctive, and look, you have seen one of the competitors that have got approval for treatment of MDD is a combination of two different antidepressants. The indication we are pursuing is treatment of patients affected by major depression who have not responded adequately to the current treatment they are on. The doctor will decide if it's going to be add-on or if they will stop the nonperforming antidepressant and replace it with REL-1017. So we are looking for a broader label treatment of depression.

Jay Olson, Analyst

Okay. That's helpful. And then is there any color you could provide around what percent of patients in the RELIANCE studies have opted into the open-label extension?

Sergio Traversa, CEO

At the moment, I don't have that number readily available. Maged, do you have the figure?

Maged Shenouda, CFO

So broadly, the numbers that we have is about 75% of the patients have opted into going into the open-label study.

Sergio Traversa, CEO

That's for all the trials, though, not specifically to monotherapy.

Jay Olson, Analyst

Okay, great. Thank you. That’s helpful. Thanks for taking the question.

Sergio Traversa, CEO

Last time, we had around 600 patients in the long-term safety now?

Maged Shenouda, CFO

Yes.

Joon Lee, Analyst

Hi. Thanks for taking my questions. Do you have any data comparing the PK/PD of powder formulation to tablet formulations from REL-1017?

Sergio Traversa, CEO

Yes. Thank you, Joon. We will. But I believe Dr. Manfredi and the team looked at the PK profile. There’s no difference between powder and the tablet.

Joon Lee, Analyst

PK profile, powder and tablet. Got you.

Sergio Traversa, CEO

Yes. We have the powder in solution based on the Phase II data, and we examined the profile in monotherapy and the blood levels; there is no difference.

Joon Lee, Analyst

Okay. In the press release, you mention that you now expect these results in 2023. Does this refer to RELIANCE II? If so, wasn't it always anticipated that we would see this in 2022 or 2023?

Sergio Traversa, CEO

At this stage, we prefer not to specify whether it will be in the first or second half of the year. Currently, RELIANCE II is about 25% enrolled, but our main focus has been on monotherapy. We have dedicated significant resources, advertising, and energy to complete the monotherapy. RELIANCE II has not been expedited for enrollment because we wanted to monitor the progress of the other two studies. Therefore, in 2023, RELIANCE II will become our main focus. We are also considering a similar Phase III study, which we will finalize after analyzing the results from the 301 study. We anticipate completing RELIANCE II within 2023, and after we receive the data from RELIANCE I in December, we will provide more detailed plans.

Joon Lee, Analyst

Great. Thank you so much.

Sergio Traversa, CEO

Thank you, Joon.

Operator, Operator

And that does conclude today's question-and-answer session. I would like to turn things back to Sergio for any closing comments.

Sergio Traversa, CEO

Well, thank you all, and thank you, Dr. Fava. Thank you to the team. In closing, I really remain grateful to the Relmada team for their continued hard work and dedication to executing what is for us 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 their efforts in advancing this important product candidate to the clinic. We look forward to the RELIANCE I data and continue 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.

Operator, Operator

And with that, that does conclude today's conference call. We'd like to thank you again for your participation. You may now disconnect.