Relmada Therapeutics, Inc. (NASDAQ:RLMD) Q3 2022 Earnings Call Transcript

Relmada Therapeutics, Inc. (NASDAQ:RLMD) Q3 2022 Earnings Call Transcript November 12, 2022

Operator: 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 speakers’ remarks, there will be a question-and-answer session. And Brian Ritchie, you may begin your conference.

Brian Ritchie: 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.

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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: 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 end point of a statistically significant improvement in depression symptoms, compared to placebo as measured by the MontgomeryAsberg 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 an 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 and roughly 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 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 up. Looking further ahead, we intend to apply several plausible and operational changes in the current enrolling RELIANCE II study and make certain improvement 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 focused 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 for 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 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.

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Maged Shenouda: 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 noncash 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 over the call to Sergio. Sergio?

Sergio Traversa: 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, that can answer questions regarding the REL-1017 clinical development. Thank you, Maurizio, for joining us.

Q&A Session

Maurizio Fava: My pleasure.

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

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

Guofang Li: 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 take the FDA to get an agreement for your data analysis?

Sergio Traversa: 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. So we expect to have data before the end of the year. So it’s way too late to make any change. And now I noted in the opening remarks, there is some difference. The two factors in RELIANCE I that could make a difference. One is that the patient population is different. So these are patients not naive, 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 they are not responding adequately. So — and theoretically, and Dr. Fava can help us out on 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 are also enrolled in RELIANCE I. We don’t know how these two factors, one was it in its favor. The other one may not be in favor, how they will balance themselves. But it’s way too late to make any change. We want to see what the result will look like. And sorry, can you repeat the second part of your question?

Guofang Li: Yes. Just wondering what’s your current plan for data analysis? Is it going to be the same for like RELIANCE III?

Sergio Traversa: Yes. Yes, the same. We 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 analogy will be the same as RELIANCE III with allcomers.

Guofang Li: Got it. That’s very helpful. Thank you.

Sergio Traversa: Thank you.

Operator: And next, we’ll take our question from Uy Ear of Mizuho.

Uy Ear: Hi, guys. Thanks for taking my question. Just wanted to get a better understanding of the — I guess the diagnostics or the tools that were used to assess the incoming patients in RELIANCE III, whether the tool captures some patients who are — have been chronically depressed or are episodically depressed? They’ve not really established sort of like 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. And could you tell us whether you enroll the expected number of patients and whether the DSMB has asked you to stop enrollment? Or is it — do you think it’s sufficiently powered? Just wanted to get a better sense of what’s going on there. Thanks.

Sergio Traversa: Sure. Thanks for the important question. Dr. Fava, you may take the first one, you help us how to analyze this data. So please go ahead. I will then answer the second question. Please go ahead.

Maurizio Fava: Sure. So it’s a great question. I’m Maurizio Fava, the Chief of Psychiatry at Mass General and the principal investigator for the studies. The — 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. And in addition, they had to be relatively lean for U.S. standards, that is they have to have a BMI between 18 and 30. And 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 kind of 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 see the tripling of anxiety and depression. So are these diseases, what we’re seeing is rise of people experiencing depression? Or are these stress-related depressive episodes that in some ways will continue to resolve? The answer — 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 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 step is caused by the pandemic.

Sergio?

Sergio Traversa: Thank you, Maurizio — Dr. Fava. And I hope that answers your question. And 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, it’s futile. So it’s not worth to proceed and add more patients that they would never be statistically significant or the trial is already statistically significant at the 220 numbers. So I mean what the DSMB recommended, it doesn’t mean anything in terms of results. No way to read if it’s because the trial will be successful or the trial will not be successful. Hope it answers also the second part of your question.

Uy Ear: Yes. Thank you very much. Thanks.

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

Yatin Suneja: Hey, guys. Just a couple of questions for me, just to clarify. So what percent — 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, you seem 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?

Sergio Traversa: Yes. Thank you, Yatin. I got the question. And the — in terms of overlapping of size, I don’t have the exact number, but there is the best — like I would say that overlapping is pretty high between monotherapy and RELIANCE I. The one that really matters, the sites that have a high — they enrolled a lot of patients, the high enrolling sites, and they are the one that have this paradoxical response where placebo outperformed the drug by quite a bit, and it’s kind of isolated to a few sites. But these are the ones that really could make the difference. We don’t know — I mean the site are in RELIANCE I as well, but we don’t know if the phenomena is going to be the same or not. As Dr. Fava was saying, this is a different patient population.

So this size may have different results, but we won’t know it until we see it. And the — we discussed about expanding the enrollment in RELIANCE I with the DSMB recommendation. If the site — or if the trial is somewhat compromised, adding more patients will just expand time, cost, and probably, unless we tripled or doubled number of patients, won’t make it such a big difference. So it’s much more productive to just see how the results look like, learn from the result. And eventually, you’ll likely start 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. So the decision was really just let’s see how the data look like as the profile of the patient is different.

Yatin Suneja: Got it. And then 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 going to yield?

Sergio Traversa: Well, clearly, RELIANCE — 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. So in changing the way the rating is done from a localized to most likely a lot less localized rating. So we are implementing these changes, but technically, the trial is open. We only enroll 25% roughly of the full patient population. So RELIANCE II is still a very valuable trial. The site and the similarity with RELIANCE I and III, the site that they affected RELIANCE III that are not in RELIANCE II. And so that’s already an indication the number of patients is low. So that’s a perfectly non — we don’t think it’s a compromised study, that we’ll continue to enroll, and we expect to complete and have data sometime next year, probably. I hope I answered your question.

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

Andrea Tan: Hey, Sergio, thanks for taking my question.

Sergio Traversa: Hi, Andrea.

Andrea Tan: 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 these improvements that you were speaking about for RELIANCE II?

Sergio Traversa: 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 them commercial sites, but they enroll patient 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: Yes. No, it’s a great question. I think that — 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 So if I am 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’ve tried before. But if I’ve never been treated before, I may respond to an ad. I may look at a study. So whenever you’re doing a study that 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, at least in prior episodes, have shown that they’ve responded only to medicines. You’re likely to have what we call abnormal placebo responses. And the abnormal placebo responses are due to spontaneous remissions that may have happened at any point during the study. So the same site that may have performed terribly by enrolling these people who have 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. So 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, 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. So it’s like a different disease altogether. And so I don’t know if I would predict that the same size that performed badly on the monotherapy trial are going to 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.

Andrea Tan: 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 maybe mitigate some of those issues or caught people that 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?

Maurizio Fava: Yes. I think that —

Sergio Traversa: Dr. Fava, it’s really for you.

Maurizio Fava: I’m pretty confident that for the SAFER would clearly protect you from high placebo response rates in patients who are currently treated. In patients who are untreated, the — normally, a SAFER interview determines what medicines you’re on, how the — 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 with acute episode, the question — 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 to chronic or recurrent.

And therefore, you’re in a situation of high stress like the pandemic, COVID-19. 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 have been assigned to active treatment, right? Instead of the placebo in those sites where they outperformed the placebo, outperformed the drug, the drug would have looked fantastic. So you often hope the randomization takes care of it. But at the level of 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: 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 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? Thank you so much.

Sergio Traversa: Yes. No, thank you, Andrea. Look, as much as I wish, we really need — we want to see RELIANCE I data result before and — before we make any decision. Because moving forward, we’ll probably go — continue to go into the treatment of patients that did not respond adequately to a treatment. And so the RELIANCE I data, very important critical to understand how we will move forward. The FDA, we believe they will want too positive Phase III data. So we’ll be planning accordingly. Because in depression, it’s not unusual to have failed study and they had, I believe, three out of five failed studies and the first two Prozac studies failed. So it hurts when that affect directly, but it’s not very unusual. So we will really base the plan based on the first adjunctive trial result.

And we are planning to start at least one more trial, but we will a lot more precise in January after we see the 301 data in — 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.

Andrea Tan: Great. Thanks everyone.

Sergio Traversa: Thanks, Andrea.

Operator: And now we will move to Andrew Tsai, Jefferies.

Andrew Tsai: 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: Yes. Thanks, Andrew, for the question. It’s a little bit difficult to answer precisely. But like the — roughly the site that had results that we define paradoxical, the placebo outperformed the drug for whatever reason. And they enrolled about between 25% and 30% of the patient in RELIANCE III in the monotherapy. In the first adjunctive, it’s unfair to make a comparison with the same site because as Dr. Fava said, the patient population is different. So these sites, clearly, they enrolled 30% — between 30% and 40% of the patients. But the patient population is different, then we don’t know how these studies really perform the diagnostic of the patient. And it may be different. We hope it’s going to be different from monotherapy.

But in terms of like the percent of patients was between 25% and 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 trigger one — the first adjunctive trial. None of these sites is in RELIANCE II.

Andrew Tsai: Okay. None other sites. Okay. And so I guess, maybe a bigger-picture question is, is this 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.

Sergio Traversa: Dr. Fava, can you help me out on this? You are really the expert.

Maurizio Fava: Sure. So if you look at approved antidepressants, all the meta analysis have shown that about 40% of the proved antidepressants were — 40% of the trials were positive. And 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. So an analysis by show that when you have placebo response rates above 40%, you tend to lose the ability to detect a signal. And 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. And if you are simply looking at an acute major depressive episode, those patients that have a response to the stress do meet criteria.

So unless you specify that you want chronic and recurrent depression in monotherapy, unless you specify — 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. And I apologize, Sergio, but I have another call at 5:15. So I only have three minutes left.

Sergio Traversa: Thank you, Maurizio. Highly appreciate it.

Andrew Tsai: And one last one is just the cadence of the event. So it 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? And then would be those certain improvements?

Sergio Traversa: Yes. Thanks, Andrew. At this time — well, first, we really want to see the RELIANCE I result. And — but at this point, we don’t think there is really any need to meet with the FDA because the changes plan that we are actually implementing in RELIANCE II and most likely in any of the trial, who will do more additional trial in the future, they’re not FDA-depending. It’s really purely operational. Like nearly, I can give you some examples a few of them, but they’re limiting the number of patients enrolled per site. Like when a site enrolls four patients and do an audit and see how things are going to be sure that the site perform at the maximum level. We probably we are making some change in the ratings, and the decentralized rating may add maybe too much variability, and we may centralize more of the rating.

There are quite a bit of — the protocol, 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 would be also easier for the site to enroll patients. Now we can go on, on all these, but these are all operational non-FDA-related changes. Nothing is to tell.

Maurizio Fava: And Sergio, if 301 is positive, then we won’t necessarily to have make major operational changes to III or II.

Sergio Traversa: Correct.

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

Sergio Traversa: Correct. Correct.

Andrew Tsai: Okay, all right. Thank you —

Sergio Traversa: But one comment I would not really focus on catabolized sites. It’s more the current situation. And we’ll see how RELIANCE I looks like, but it could be that these sites could have performed very well in RELIANCE I. So it’s more like the complexity of the 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 is not the first depression trial they have 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 was mainly responsible. Clearly, if these sites would have been limited to a single-digit patient and not to 20 plus, the impact would have been lower. But again, we’ll see what Tier 1 looks like before we make major amendment.

Andrew Tsai: Very clear. Okay, thank you.

Operator: And now we will go to Jay Olson of Oppenheimer.

Sergio Traversa: Hey, Jay.

Jay Olson: 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: 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, some create a difference between adjunctive, and look the — you have seen one of the competitors that have got approval for treatment of MDD is a combination of 2 different antidepressants. And so the indication that we are pursuing is treatment of patient effected a major depression that have not responded adequately to the current treatment they are on. And then the doctor will decide if it’s going to be add on or it will stop the nonperforming antidepressant and replace with REL-1017 or — so we are looking for a more broader label. The trial will be done in patients that have been performing with the current treatment, also because there, the diagnosis is a lot more precise.

And there is a lot more confidence that these patients are really affected by major depression and not by personality disorder, anxiety or other similar depressions that can be confused with major depression. If we’ll be successful, it’s going to be like a broader label treatment of depression.

Jay Olson: 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: In the moment — that’s a good way — no, I don’t have that number on the top of my head. Maged, may — is the number — we —

Maged Shenouda: So they — broadly. The numbers that we have is about 75% of the patients have opted into going into the open-label study. So —

Sergio Traversa: That’s for all the trials, though, not specifically to monotherapy.

Jay Olson: Okay, great. Thank you, that’s helpful. Thanks for taking the question.

Sergio Traversa: Last time, we have around 600 patients in the long-term safety now?

Maged Shenouda: Yes.

Jay Olson: Okay. Super helpful. Thank you.

Sergio Traversa: Thank you, Jay.

Operator: And now we will go to Joon Lee of Truist Securities.

Joon Lee: 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: Yes. Thank you, Joon. We will. But I believe the Dr. Manfredi and the team, they look at the PK profile. There is no difference between powder and the tablet.

Joon Lee: PK profile, powder and tablet. Got you.

Sergio Traversa: Yes. Well, we have the powder in solution for — from the Phase II data and the — we look at the profile in monotherapy and the blood levels, there is no difference.

Joon Lee: Okay. And in the press release, you say that you now expect these results in 2023. Is that referring to RELIANCE II? And if so, wasn’t that always the case that we could expect that in 2022 — ’23?

Sergio Traversa: Well, yes, the — we don’t — at this point, we would 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, really on monotherapy. We’ve given a lot of effort, a lot of advertising and a lot of energy in completing monotherapy. And so — and then RELIANCE I so RELIANCE II has always been not slowed down, but not pushed to enroll fast because we wanted to see how the other two go. So now in 2023, RELIANCE II will be the focus. And eventually, with maybe another Phase III similar study that we’ll decide after the 301 results. So we expect we should be able to complete it within 2023. But after RELIANCE I data in December, we’ll be a lot more specific on what the plan is.

Joon Lee: Great. Thank you so much.

Sergio Traversa: Thank you, Joon.

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: Well, thank you all, and thank you, Dr. Fava. Thank you to the team. And in closing, I really remain grateful to the Relmada team for their continued hard work and dedication to executing what is for us is really a mission. And 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 to the clinic. And 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.

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.