We're gonna get started on our next session. Good morning. Thanks for joining. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have the Relmada team with me. To my direct left, Sergio Traversa, CEO, and to his left, Maged Shenouda, CFO. Welcome.
Thank you. Great to be here.
Well, thank you. Thank you, Jefferies, and thank you, Andrew, for the invitation.
Of course. So, would you like to spend a couple minutes talking about the Relmada story? Just give us an introduction about what you're working on, what the drug is, and the milestones coming up.
Yeah, sure. Well, first of all, a good morning to everyone. It's an early morning in the United States, and or a good late morning or early afternoon somewhere else on the other side of the ocean. Relmada. So at the key program of Relmada, what we have been working for now close to 10 years, is REL-1017. It's a very interesting molecule that work as a once-a-day oral NMDA antagonist that we have been developing for the treatment, adjunctive treatment of depression. So a patient that does not respond appropriately to the first or one of the cycle of treatment like SSRI, SNRI, and is added the REL-1017 at one tablet in the morning.
And the result that we have seen from phase I, and especially phase II, and somewhat the phase III that we run, the first two phase III, has shown that, you know, there is a very nice, very good improvement in the depression symptom of the patients. And there is no antidepressant approved as a adjunctive treatment. There are, I believe, four drugs now approved in the United States, and they're all antipsychotic. So there is a clear need and space for a new, safe and well-tolerated and effective antidepressant in that space. We did all the development. We run phase I, phase II with very good data, two phase III trial back in 2021 and 2022.
The results were not, for a variety of reasons, mainly, we ran the trial during the COVID period. They show some good data, but they're not good enough to file an NDA. So, we have been well-financed, and we are well-financed, so we are rerunning two phase three trial, and, you know, we are applying everything we have learned from the two previous trial. We are in late stage development in phase three, and we'll expect to have data for the first one in the second half of this year.
Great. So before we dig into the phase III trials, maybe one question about the market opportunity. You said there's no SSRIs approved for adjunct MDD, but there are antipsychotics. So maybe compare, contrast the profile of REL-1017 to antipsychotics.
Yeah, sure. There is actually no antidepressant approved as a, as adjunctive treatment for depression. There are antipsychotic, and they have shown some efficacy as adjunctive treatment of depression. However, as we all know, antipsychotic, they have a profile, especially on the long, long term, on the safety side, that is not optimal for patients that have to take the drug, for weeks, months, and sometimes years, and namely, like, metabolic issues a nd so the big difference in REL-1017, we do believe that at least based on phase two, the efficacy is has been shown with REL-1017, but the safety profile is extremely benign. So far, we have treated over 1,500 patient.
We have seen no one single serious side effect. The major side effect at high dose is nausea, transient nausea. So, we do believe that the once a day and the safety profile very benign of REL-1017, combined with a, you know, very, very good efficacy profile, will make it a very good additional entry in the additional treatment for depression. And the market opportunity, I mean, there are numbers that can vary depending on the source, but there are 15 million-20 million patients affected by depression in the United States only, and only about 1/3 to 1/2 they respond reasonably well to current therapies.
The market opportunity as an adjunctive treatment is easily in the 4 million-5 million patients in the United States.
Makes sense. So as we wait for the phase III data, just in the meantime, you know, what kinds of phase I studies have you done so far, and are there any other peripheral studies you need to do before filing the NDA after the phase III data?
Yeah. Thanks, Andrew. We have done all the development required to file the NDA. That means all the traditional safety phase one studies, single dose, multiple dose, and we have completed the—I believe it's the most extensive abuse program ever done for a drug, and they've shown that despite the name esmethadone, the drug has shown a very clean abuse profile. And we have seen it also in the phase two and phase III and phase one data. There is no sign of any, no one single patient that tried to abuse or inappropriate use REL-1017.
In terms of phase I, we also completed all the required special population phase I, meaning patients affected by liver impairment, renal impairment, drug-drug interactions, and there were, like, six or seven different trials. So they all completed. We did complete the biggest one was the 12-month safety study, and the over 600 patients showed that the drug has shown very, very good safety profile for 12 months of continuous therapy and a nice efficacy profile. So the only thing missing to file the NDA, and this is not a trivial exercise, but we miss two positive P-values of phase III trials.
Right. So you've—again, you've had those two phase III readouts. Both saw a high placebo response. So what did you exactly learn from those studies, and what are you doing differently this time?
Yeah, well, we learned a lot. Unfortunately, we had to run, and we didn't realize what the impact it would be, but we had to run these two phase III clinical trials, one in monotherapy and one as adjunctive treatment of depression, right during the COVID period. And there were things that like the oversight on the trial, on the sites, it was not feasible because you couldn't go in the clinical sites. The interviews with the patient, most of them, they were done via Zoom or via virtual. So it was a very different way to run a clinical trial, and our CRO also kind of, you know, found themselves not prepared to run a clinical trial appropriately in during the COVID period.
Appropriately mean, using everything they have learned, in their experience. And so we experienced a high placebo response. There was that, you know, we all remember the article talking about the sharp increase in the rate of depression that was like three to four times higher than normal during the COVID period. Yes, there was a lot more people have symptoms, depression-like, but it was not really depression, and this affected also the results of our trial, specifically the placebo response. It was our patients that felt like their sleep disturbs, appetite, and bad mood, but was related with the situation, not really with the biological status of depression.
So that by itself should help the results of the current ongoing phase III clinical program. With that said, we also implemented quite a bit of, we call them improvement in how we run the clinical trial. There is clearly more oversights because now you actually can go in the clinical sites and talk with the investigator, and there is an exchange of information and to run the you know to include the right patients. So the major changes, improvement have been on three different areas. One, the protocol, the patients, and the site selection. In terms of protocol, we now have a very large amount of safety data, over 1,500 patients treated.
So there is no more requirement to do a lot of ECGs and a lot of items in the old protocol that were required because of, you know, we needed some experience for the FDA. Now, all that is not there anymore, so the protocol has been simplified significantly. That translate in much less contact between the patients and the clinical site investigator, that it should reduce by itself the impact on the placebo response. And so a simple protocol. And in terms of site selection, we have the luxury that we have been working with over 100 sites, and we do have proprietary data about how these sites they behaved during the previous phase II trial.
So we use this data to optimize the site selection. We also, we do have some new sites. We don't have the sites that unfortunately not many, but they have impacted the results of the other two trials. We do believe that the biggest change and improvement is in the patient selection. There was probably the major underlying issue that we experienced in the previous clinical trial. So now the biggest change, the biggest improvement is the requirement for medical and pharmacy record. In the post-hoc analysis of the previous trial, we noticed a big difference, in terms of placebo response and overall results in patients that came from, we call them, verifiable sources.
In reality, it's patients that were referred by—they were known by the sites in their database or were referred by physicians and by. They came from a medical source, while the patients that were not coming from these sources were coming from social media, they didn't show the same results. So now, every patient that wants to be enrolled in the study has to provide medical record, meaning who's your doctor, and show me the document that show that your, you know, family doctor or whoever treats you has diagnosed you with depression and pharmacy record. Show me that, for the—we have record up to back to two years of pharmacy.
Show me that you, you have actually purchased antidepressant in a pharmacy. That by itself should make a big difference because we now feel confident that the patient enroll, the vast majority of them, is really affected by biological depressions.
What percentage of patients in the prior phase III studies were verifiable?
About half. About half of the patients.
I see. And it's, it sounds like you do have more oversight with these studies. What exactly are you monitoring on a daily or weekly basis, to ensure site quality and patient quality?
Yeah. So in monitoring a few parameters, let's put it that way. Like the blinded data, they don't really tell you much about efficacy, but, you know, sometimes they can tell you if there is an issue, right? One typical potential issue is when you have a patient that does the MADRS scale that monitor the amount or how serious are the depression symptoms. And usually placebo has a profile, and the drug has a profile. But when you see a patient that has, like, week over week changes, like they do zigzag, like up and down, that's one of the symptoms that tells you something is not right there.
And clearly we speak with the sites, how the sites collect the data, how they like how organized they are. It's all quality parameter. There is no one single item, right, that tell you this site is a good site or is not a good site. And so it's a combination of that. We do have full-time people that about 15. They actually go every couple of weeks to visit the sites and talk with the investigator. So all this was not possible before, and it is possible now, and we are doing that. So we also limit the number of patients per site. One of the issue that we experienced before, there were a few sites that were outlier. They were enrolling fast. They were enrolling a lot.
They enrolled a lot of patients, and some of them did not show, right? A few of them, they didn't show very, very good results. So we avoid that risk of being dependent on, like, one or two or a small number of sites that enroll a lot of patients, and we try to spread out the patient enrollment.
Great. Remind us, where are you on enrollment for the first phase III study coming up?
We expect data in the second half of this year.
Second half.
Right.
This is a four-week study, maybe another four to eight weeks to clean the data. Worst case, if data comes by year-end, within the second half guidance, you would finish enrolling October?
Yeah, I mean, we are cleaning the data in real time, so, you know, the, when we close the database to the data, it should not be like w e don't expect two months, right? It's gonna be much shorter than that.
I see. And, how much further behind is the second phase III study relative to the first one?
We expect data about six months after the data from the first study.
I see. So it would not make sense to combine the two data sets together into a top-line release. They're too far stacked.
No, it doesn't, like w e would rather do it separately because we still may learn something in the in study three or two that we closed earlier, that we may apply to the second one.
Then in the first study, technically, 100 patients were already enrolled before you made these changes to the protocol.
Correct.
And so, do you have more confidence in the second study where you've, you know, there's no prior patients?
Well, difficult to say, but you know, we have really no reason to believe that the first 80, 90 patients that were enrolled previously of the protocol amendment would not have good data. Consider that there was a very sharp difference in results when the COVID restrictions were lifted, meaning after patient enroll after April, May 2022, to the end of the study, that was September, they showed very, very good results. And so, the half of the patient enrolled previously of the protocol amendment have been enrolled after the COVID restrictions were lifted. Well, clearly, we don't know anything about the data, but we don't really have reason to think that they should not be good data.
Okay. What kind of average baseline MADRS score should we expect for these phase III studies, and how does that compare to the prior two phase III studies?
When we look at the blinded data, that's pretty consistent, like, 33, 34, baseline.
That is in line with what we have seen in the previous data.
How are dropout rates looking comparable to the prior phase III data?
Yeah. Yeah, thanks, Andrew. It is comparable. We always experience a very low dropout rate, meaning the drug is well-tolerated and is once a day, so it's... There have never been issues in compliance, and so I think it's definitely single digit. I know Maged has more recent information.
It's about 6%.
Yeah, about 6%.
6%.
It's in line with, you know, historical low rate of dropout.
Great, and screen failure rates, where are they and how does that compare?
Yeah, that's why it doesn't compare well, actually compare well, very well with the previous study. So in the previous study, the screening failure is the number of patients that get screened and versus the number of patients actually enroll, was about half. So about 50% of the patients screened, they were enrolled. With the, I don't wanna call them restriction. I would call, like with improvement in the patient's adjudication process that we applied to the current clinical trial. This, you know, screening failure has gone up to the 75%-80%.
And that means that we enroll about two patients every 10 patients screened. That we see it as a positive because the adjudication process is very rigorous, and we do believe that, you know, the two patient that we enroll are, you know, are patient that they should be in the clinical trial.
Right.
So, that one is something that, although it looks like a big number, looking at the 80% screen failure, we see that is a reflection of the quality of the patient enrolled.
Right. You're not taking shortcuts or anything like that?
No, no, they don't.
Right. You know, as I think about the overall landscape, it does seem like there seems—you know, the enrollment for MDD patients seems competitive in a sense. Are you seeing that within your high-quality sites?
Yes, we do, but you know, every clinical trial has its own like, patient profile, and REL-1017 is developed as adjunctive treatment, so it, it's compatible with the competitive landscape.
Got it, and how, how often is the DMC looking at the data?
Yeah, thanks, Andrew, for the question because this is something that I would like to emphasize today in the call. The DMC in the previous trial was meeting every quarter, I believe, but only for safety.
We have not experienced any safety concern, so that is not a requirement anymore. But what we are planning to do, what we are planning to have is an interim view of the data from the data monitoring committee, and that is a sample re-estimation. So there is no chance for early stop or it's not... We don't want to pay any statistical penalty in taking a look at the data before, but it's a sample re-estimation. And so at some point, and the closer you get to the end of the study, clearly, the better is to have the more information gives you this sample re-estimation. And so we are planning to do that about, you know, 75 or 80% of the patient enrolled.
What the DMC, they will see the unblinded data, and they will tell us if the number of patients planned for the clinical trial, that is 300 patients, is good enough to get to a statistically significant P-value or if we need to add some patients.
Now, if they tell us that we are good with the 300 patient sample estimation, they will not tell us if the drug works or not. They will only tell that we can stop at 300, and there is still, like, the possibility then the study can be futile, and they will not tell us.
So, if we are good to stop at 300, that doesn't mean that the drug works, but it can be futile. But the statistical plan is set in a certain way that the risk of stopping the trial at the planned 300 patients for futility is very, very low.
I see. So best scenario, ideally, would be no change or no upsize in enrollment, but you still don't know if it's futile or not at that point?
Correct. But you know, the chances that it is futile at 300 patients, based on the statistical plan that is used by the DMC, is very low.
Is this something that you would plan to share with the street?
We will. We will share. It's material information.
Okay.
We'll share.
Is there any reason to think, you know, REL-1017, the drug behavior on MADRS and these new phase, new improved phase III studies could do better than what you saw in the prior phase III study?
Well, on the average, we believe so because we are trying to enroll patients affected by biological depression, by real depression, and not from transient or reactive depression. And REL-1017 works very well in patient really affected by depression, so we expect good.
At the same time, placebo should not work very well in patients affected by biological depression.
Right. And where do you think placebo should then fall in these new phase III studies relative to the prior studies?
Yeah, that's a great question. Actually, Andrew, you did a very extensive analysis, historical, of placebo response in depression trial. In adjunctive treatment, the historical placebo response is between 8 and 10 points decrease of MADRS scale from baseline. And so, but we do expect that. I mean, if we can achieve like 10 points placebo response from baseline, that would be like in the range of the historical range, and then with the compared with what we expect REL-1017 decrease from baseline can do and should do, that would show a nice delta from placebo.
Right. Nice delta because the drug in the prior studies did show 15, 16, or?
Right, even higher than that.
Wow. Okay, are these studies powered to show around a two-point difference, drug versus placebo?
Correct. Depending on the standard deviation, but between two and 2.5 points.
I see. And how does the second study, aside from, you know, completely starting from scratch, how does that study differ from the first study, if at all?
It's pretty much the same.
Same.
Yeah.
Yeah. And, this is a four-week primary endpoint. Is there... What's the significance of the day seven endpoint to you?
Well, it would be nice to have a statistical value at day seven, and but in any case, if there is a response, usually the FDA puts some note or the graph on the label.
So it would be nice to have a P-value, but there is no P-value. It's to show a progression in the first week would be a nice addition.
I see.
Clearly, the 28 days is what the FDA really cares about.
Right. And best-case scenario, let's just say both phase III's worked. The earliest you submit an NDA would be second half of 2025?
Probably.
Yeah. And then maybe last question, just patents for 1017?
Yeah, patents, we have a good patent stage. We continue to work on that. The key patent is a use patent, that I believe expires in 2033. First expiration, then we do believe we'll get some extension for, recovery of the development time. It can go up to five years. And so that's the first patent. So mid- to late-2030s should be the first expiration. There is other patent filed, and but that one is the one that is the more the first one that will expire, about like 10, 12 years from now. It is a new chemical entity, so the worst-case scenario, excluding any patent, the drug has an exclusivity in the United States of, 7.5 to eight years.
That would be five years for a new chemical entity, 30 months for the stay from generics, and 6 months for pediatric extension that we are planning to do.
Got it. Just really quickly, you guys do have the cash to see through these things?
Well, I'll let my CFO to address that.
Yeah. So last quarter, we reported $83.6 million of cash on the books, and what we've said is this can take us out to 2025.
Great. Okay, well, thank you so much. Fingers crossed with this upcoming read out.
Thank you.
Thank you.
Thanks, everyone, for tuning in.
Thank you, everyone.