Tuning in. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Next up is Relmada. To my direct right, we have Sergio Traversa, CEO, and to his right, Maged Shenouda. Welcome, both of you.
Thank you, Andrew. Thank you as always. And good morning here, and good early morning in the United States. Very nice meeting.
Great. Maybe spend a couple of minutes talking about the Relmada story, where you are in the clinic, and what data you've generated, and what kind of catalysts we can expect.
You want me to do it? Yes.
Sure.
Relmada is a NASDAQ company. We have been listed since 2019. The focus has been from the very first day on CNS, Central Nervous System diseases, depression in particular. The key program has been Relmada 1017, or esmethadone, that we have been developing from the very, very early stage, from making the manufacturing, all the preclinical, extensive phase one, great phase two, and we are now in the, I would say, the fourth phase study, including long-term safety.
And we had, historically, we had good data, except the last two phase three that are very, very important, where we had data, I would say, that got very close to be statistically significant, but they did not, and so we have been nicely capitalized, and so we had repeated to repeat the program.
We are now in the very, very late stage of the first of the remaining two phase 3 trials. We expect a very important interim data within, we said, before year-end. It means that it is within the next two, three, four weeks.
Wonderful. And before we dive into the phase three programs, just high level, Relmada 1017 differentiation as an adjunct of MDD. What is the ultimate goal here?
Yeah, we feel very good about that. Relmada 1017 is a once-a-day oral tablet that we have been developing for a very targeted indication, this adjunctive treatment of major depression, or MDD. We emphasized adjunctive treatment because there is no antidepressant, oral antidepressant approved currently for this indication. There are, I believe, now four products, and they're all antipsychotic with the benefit and also the issue related with long-term therapies with antipsychotic.
So if we can demonstrate efficacy, and we do believe we have demonstrated very good safety, but if we can and hope demonstrate efficacy as well and get approval, Relmada 1017 will be the first oral treatment for adjunctive treatment of major depression. So it's a very clear indication, and patient population in the United States, it's about 40% of the patient they require a second combination therapy for depression.
We are talking about four to five million patients in the U.S. alone, as many in Europe. It's a very, very attractive market, patient population. We hope to be the first of addressing the issues with this indication.
Great. And newer investors to the story will naturally think, is the drug working or not? But when you look at the phase 3 data, what exactly went wrong?
As usually happens, there is no one single reason that created such a problem. It's usually not our style, and we usually don't look for excuses. We have always been very direct, and we tend to be, we want to be as honest as possible. But in this case, we have to believe, based on data, that the COVID situation has heavily affected the clinical trials, especially the second clinical trial, the Study 301, that was an adjunctive treatment of depression.
We say that because, number one, we have not been the only company being affected. Many companies that have run phase three trials during the COVID pandemic had data that are difficult to explain. We have not been the first. We have not been the last. That was clearly a factor.
We say that because we have looked at the data in the same trial with the same patient population, the same everything, so no real changes. Data before the lift of the COVID-related restriction and after, and the difference is extremely, it's difficult to believe when you see it. That was clearly the major component that translated in consequences.
There have been patient population that was not affected by major depression, but were more affected by reactive depression to the situation that, of course, can benefit for everything. Just walking out the door and going to clinic or talking with the doctor was benefiting these patients. That's ultimately translated in a very high placebo response that masqueraded the effect of the drug.
Yeah, because when I look at it, the phase two, phase three efficacy, the absolute MADRS reduction that you're achieving is consistent and tight.
Correct.
Yeah. And to your point about other companies, I mean, just another one unfortunately failed because there are professional patients in their study. So maybe that has, to your point, you're not alone kind of thing. And so now you have these two phase 3 studies ongoing. Again, the first one, like you said, has an interim readout. So before we get to that precise interim and discuss about it, what exactly have you done then to control and mitigate against a high placebo effect?
Right. We've made a lot of adjustment from what we learned from the previous trials, and we can divide the adjustment in three different kind of activities or kind of aspects. One is the protocol. It's well known that the more complicated is the protocol, the more the patient is involved with the doctor and with the trial, the higher is the placebo response.
We now learned a lot about safety, and the current protocol is not requiring all the scales or the informational aspect that were required in the previous trial, so the protocol has been simplified significantly. Site selection, we also look at data by sites, and we couldn't find a specific reason, but out of 43 sites that we had involved in the trial, two sites had results that were not consistent with the other 41.
These two sites alone, clearly involuntarily, but they made the trial not being statistically significant based on their data. So we now have proprietary data on sites, about 100-110 sites that participated in the previous clinical trials. We do know, and we have selected clearly the sites that have demonstrated they can control placebo response. That was the same angle that we have improved.
The third one, that is the summary of the other two, and two results in the key factor, patient selection. One key factor of the patient selection is that we are trying to limit the number of patients enrolled by single sites. No single site can have a big impact on the outcome of the whole trial. We are trying to also limit or control the source of the patients in the trial that did not succeed.
We did have over half of the patients were enrolled coming from sources where the social media, like Facebook and Instagram and so on. And we look at the data, and the patients that were originated by social media had very different performance data in terms of efficacy and placebo response compared to patients coming from more medical and clinical sources. So I would say among all the changes, the key change that could or should make this trial to have better results is the requirement for medical records and pharmacy records.
It means nothing else that we want to be sure that since this one is an adjunctive treatment, so the patient has to come to the trial already in treatment with an antidepressant, that this patient has been diagnosed and prescribed an antidepressant by a clinical source, by a doctor, and that has purchased the drugs from the pharmacist for the last, I think the maximum is the last two years.
So we want to be sure these are real patients. That's the bottom line. So these three amendments and these three improvements combined, they should make a significant difference. And I say one more, the trial per protocol had a p-value of 0.051. So it really missed the p-value for a little, very, very small percentage.
Just to be clear, when you said the prior phase 3 had outlier sites, those same outlier sites are not in this current phase 3.
Yes. The two trials that were outliers. They've never been involved in this trial.
Got it. And so with these phase three studies, how much more oversight do you have as these are going on and wrapping up? Are you monitoring more or something more on a daily or weekly basis kind of thing to make sure you're controlling?
Yes, there is a lot more oversight. But I want to give you an idea that in the previous trial, there was no oversight. The oversight could not have been very close to the sites and the patients because of the COVID situation. We literally couldn't go into the sites as much as we would have liked, and the patient couldn't go into the site as much as they want. But the straight answer, yes, there is a lot more oversight compared to the previous trials.
Got it. And ultimately, what are these phase 3 studies powered to show in terms of placebo versus drug?
The answer requires a little bit more expansion. As we always said, the trial is powered to detect the minimum of two-point delta between placebo and the drug. The reason of the two-point delta is that it's considered the threshold for an approval drug. Most of the antidepressants, like fluoxetine, Prozac, and so on, they show like two, two and a half points delta.
That's the threshold for an approval. Also it's considered a threshold for a clinically meaningful effect. Anything above two points would translate in an approval drug with a clinically meaningful effect. It should translate in a p-value if we did the right thing, and we think we did on the statistical plan.
Understood. And so now we have this nice interim analysis coming up, you said, in a matter of weeks. Explain the process of how it works, how many patients will it evaluate, and the scenarios that can come out of it.
Yeah, sure. The number of patients, I mean, the patient, the interim analysis, we try to do it as late as possible because clearly the latest you have the interim analysis, the more reliable is the information that you get. And so this one has been done at about 70%, a little bit more than 70% of the planned patient population.
It's somewhere around like the 300 number. And the outcome, we spent a considerable amount of time and energy and effort, and we have two very, very good statistical teams, statistical companies that worked on helping us to define a statistical plan that would give us the information that we need to drive a successful study. And so the outcome is three different outcomes. I start from the one that we don't like, that is futility. We are still reasonably good capitalized.
At the very minimum, we want to know if the study or the trial has a chance to be successful or not. Because if it does not, to be very open, there is not much more that we can do to make a trial run better. This trial has been run by the book with all the attention and that are required.
Even with everything we have done, we want to know if whatever we have done has been useful and translated in a delta from placebo above the two points. The first outcome is futility. That's what we'll know for sure, if the trial is futile or not. If the trial is not futile, then there is, at the other extreme, the best outcome is continue as planned.
Continue as planned, that will mean that we will have somewhere between 80%-90% or above statistical power to have a successful study. That is very, very high. So you need a 50% conditional power to have a p-value below 0.05. So I mean, the outcome will be continue as planned.
It means that we'll have 80-90% chances to succeed. It is not risk-exempt because the trial is not finished, so there's still a certain number of patients that need to be enrolled. So it's not 100%, but the chances would be relatively high. As a parachute, we put a third outcome that we did not have in the other studies, that is enroll more patients.
If the DMC, the Data Management Committee, will inform us that we are close to have a powerful enough study, but we are not there yet, there is a chance that will tell us add X number of patients. And then this outcome, depending on how many patients we will have to add, it can be reasonably good. If it can be good, it cannot be not great, but still it will have a chance to get a p-value at the end of the study.
I see. And so futility threshold is below two points. Continue as planned versus small upsize. What kind of efficacy delta are we talking about for those two scenarios?
Yeah, it gets complicated in the detailed statistic, but to make it very simple and easy to understand, between two and three points delta from placebo, it's going to be the second option to add patients. And the closest is to three points delta, clearly the last patient we have to enroll. Anywhere above three points would be continue as planned.
I see. Wow, and in the modest or just the upsize scenario, chances are it's just a modest upsize, not some kind of extreme number in terms of more patients or else it might not work out, or how many more patients could you be adding?
I want to give you the exact number because there are so many scenarios we spend the rest of the day to go through each of them. But in reality, what we look is also something that is feasible. A trial, even with a minimal delta, let's say one point from placebo, you enroll 700-800 patients, you can make it statistically significant, not clinical, but statistically significant.
But that's also not very operationally feasible. So I would say usually the maximum you go is 50% above what is the target number for a successful study. And we said it's about 300 patients. So I mean, doing the math is like about 50% above that.
Noted. Noted. And to be clear, there is no alpha spending for this interim?
Yes, there is no actual spending. And the reason that there is no alpha spending is there is no early stop of the trial. So the DMC does not have the option to tell us, even if there is already a p-value, they will not tell us, "stop the trial now." So that avoids paying a statistical penalty that we don't want to do.
Let's say in the scenario where it is continue as planned, do you move aggressively in the regulatory filing front? Or are you waiting for the final data readout? And when would the final data readout be?
We will definitely wait for the final data also because if it is contingency plan, the final data will come, I would say, in the first half of next year. We will be very careful about doing everything right, but the number of patients to enroll will not be that high. We expect by mid next year to be done with that.
We have to wait. We will wait for the final data. Then I think your question is if we can start the filing. We have a rolling NDA because we have fast track designation. We can file the NDA in modules. The question is when we will start. It really depends on how good the data look like. I mean, if there is a big delta from placebo with a very low, very small p-value, it's worth a conversation with the FDA, and that will guide us on when we can actually file an NDA.
Speaking of this interim, can you remind me of last time you did also have an interim analysis in one of your phase 3 studies? How is it different, I guess?
It is. Thanks for the question. It is very different. First, the previous interim analysis was done at about half of the trial. That is way early in the one we have now. And there was no futility outcome. So when they told us you can stop at the earliest of the stop point, there was 220 patients, we did not know if it was for efficacy or was for futility.
And it was actually for somewhat futility that was also an outcome that penalized the whole program because the DMC only saw data in the interim analysis of patient enrolling through the COVID pandemic.
This data, placebo was very similar to the drug. And that made their recommendation based on this data. What they couldn't see because they were not available, they were not there yet, was the patient enrolled after the lifting of the COVID restriction. The delta from placebo was approximately six points. It was day and night from two different periods. The only change was really COVID. There was nothing else difference.
I see. You have another phase 3 in the background. When do we get data for that one?
We are planning about six months after we'll get data from the phase 3.
Okay. And so far, dropout rates, how are they looking on a blinded basis? Higher, below, first two?
The dropout, and we don't really read anything into that, but it is lower than the previous trial. Previous trial was like 11%-12%. Now it's 5%-6%. But again, we don't want to read anything into that. Maybe one thing that I would like to emphasize is that the screening failure, that is the number of patients that are actually enrolled compared to the number of screened, is much higher.
So we had about a 50% screening failure in the previous trial that translated about enrolling one out of two patients screened. That rate is now about 80%. So we are literally enrolling one patient out of five screened. If that's translating a better quality of the patients, we should be okay.
Right. And ultimately, cash-wise, because you're doing this carefully, maybe enrollment can take time for the fourth study. But the question is, how much cash do you have to see through these studies?
I'll let our CFO to answer that.
Sure. Thanks for the question, Andrew. So what we've said is we reported about $54 million of cash on the books with the last quarter's reporting. And what we've said is this will take us into 2025 and also allow us to meet near-term catalysts.
Okay. And let's say this was approved. Is it your intention to market it alone, or are you seeking a partner? Have you thought that far yet, or?
Yeah, we did. Yes. We did think about it, and we have contingent plans. Clearly, we are planning to launch ourselves, not because we want to do it, but we want to be ready, and that's always an option that is on the table, and then we'll see how the circumstances will evolve.
Clearly, depression is a very large market, and it needs a considerable investment upfront to do justice to a drug with a very, very large potential, and so a partnership would not be off the table, but it has to be at the right terms.
Okay. And then again, this is going after adjunctive, but do you have appetite or intention to go back to monotherapy again if adjunctive did work?
It's a good question, Andrew. I want to be honest and direct. We don't, and not because we don't think the drug would work. If it works in adjunctive, it is a more difficult indication. There is a lot more reason that it should work as a monotherapy, but because of the issues that are surrounding running clinical trial in CNS and in depression in particular,
the subjectivity in monotherapy is way too high to take the risk, so we are not planning, at least pre-approval. After approval, it will be an all different situation, but for now, no, we are not planning to look at the monotherapy.
Okay. And then last question to wrap up is, you are working on another compound, non-hallucinogenic psychedelic, I believe, or psilocybin, was it?
Yes. Yes.
What's the next step for that and indication, and when do we get some data?
Sure. Well, we kept a very low profile because the focus is clearly the phase 3, and we have short-term data coming on Relmada 1017. The P11 is the symbol of the psilocybin low dose chronic treatment of psilocybin. During the development in preclinical, we saw very attractive data in the metabolic disease that is very popular these days.
We consulted with several KOLs, and they all told us, "These are good data. You should move forward." The program just entered, I believe, last week, phase 1. So we enrolled the first patients in phase 1. We expect phase 1 data early next quarter, but we do believe the drug is fairly safe. It's a very low dose. So we don't expect any issue related with that. Planning to start the phase 2 program as soon as possible.
Probably, hopefully, not too far away from when we receive the phase one data. We would like to have data in the second half of next year, efficacy data.
Okay. Great. Well, that's all the time we have. Thank you, Sergio and Maged, for joining me today. Thanks, everyone, for listening in.
Thank you all, and enjoy the rest of the day. Thank you, Andrew.