Relmada Therapeutics, Inc. (RLMD) Earnings Call Transcript & Summary

Good day, and welcome to the Relmada results of the human abuse potential study of REL-1017 versus ketamine call. Today's conference is being recorded. At this time, I would like to turn the conference over to Brian Ritchie of LifeSci Advisors. Please go ahead, sir.

Thank you, operator, and thank you all for joining us this morning. As Slide 2 states, please note that certain information discussed on the call today is covered under the safe harbor provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, 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 the annual report on Form 10-K and subsequent filings. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, February 23, 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'd like to turn the call over to the CEO, Sergio. Sergio?

Thank you, Brian, and good morning, everyone. Thank you, Brian, for taking care of the safe harbor statement, and thanks for participating in the call today. The goal of this call is to discuss the top-line data of the second and last human abuse potential study comparison with REL-1017 with control -- ketamine as the control. Jack Henningfield, that is one of the top experts in the U.S. that has been advising the FDA and running this kind of trial for 40 years, will be present the data. So I will limit myself to the introduction and a couple of opening remarks. So these data have not been surprising for us. They have been -- they confirm and support the previous data published about the subject of potential for abuse of REL-1017. The difference that this data have been generated with the studies according to the 2017 FDA guidance and at 2022 clinical and regulatory standards. This data also support, together with the oxycodone comparison trial that we published last year in July, support the DEA statement about the lack of any meaningful abuse potential for REL-1017. We do believe that the oxycodone comparative data, the risks, the schedule to potential for -- as a schedule in the regulatory FDA NDA. And we do believe that with data, the comparison with ketamine, also there is the potential for a Schedule III. So the -- overall, the program indicates that REL-1017 will be proposed Schedule V and eventually, non-schedule after the -- maybe 1 or 2 years of market experience. At this point, with no further delays, I'll let Jack to take over and to present the data. Thank you very much.

Good morning. Thank you, Sergio. Can you hear me at -- now?

Yes.

Great. Okay. I hope you can see that we will have a few slides. So I am Jack Henningfield. I'm Vice President of Research, Health Policy and Abuse Liability at Pinney Associates. And as Sergio mentioned, I've been conducting human abuse potential studies for more than 40 years, and that includes my years at the National Institute on Drug Abuse, where I headed clinical pharmacology and abuse potential assessment. And while at NIDA, I worked with the DEA and the FDA on drug scheduling issues. The human abuse potential or HAP study that we are presenting today, as Sergio mentioned, was designed according to FDA's 2017 abuse potential guidance. And we had extensive input from the FDA staff on the measures, the comparator, ketamine and so forth. The primary endpoint, as is typical in these studies, was a Drug Liking score comparison of 3 doses of REL-1017 to ketamine, which was 0.5 milligrams per kilogram intravenous. The study participants were recreational drug users with ketamine experience. Screening of the subjects, consistent with the FDA's advice, included administering placebo and 0.5 milligrams per kilogram ketamine intravenously, and then we measure liking scores. If the subjects did not rate ketamine with a score of at least 65, 50 is neutral, by the way, and at least 15 points higher than placebo on the Drug Liking scale, then they were not qualified for the study. The point is to make sure that the subjects can respond positively to a known substance of abuse, in this case, ketamine. Such FDA-recommended HAP study designs are more likely to overestimate abuse potential than to underestimate abuse potential. So the primary measure was Drug Liking or Emax, the maximum Drug Liking. We tested 3 doses of REL-1017. These were the same as in the oxycodone study that we presented last year. They were the 25-milligram therapeutic dose; 75 milligrams, which is 3x the therapeutic dose; and 150 milligrams, which is 6x the therapeutic dose and is the maximum-tolerated dose. 51 subjects completed all arms of the study. These are the completer subjects. And by the way, that's a little bit more than our typical for these studies. So this is a well-powered, well-designed study. So let's get right to the main findings. Now I don't see a table on my screen. Hopefully, you can see a table, but if you can't, let us know. I will try to explain the results carefully. The main finding was that ketamine produced large and significant increases in drug liking. In fact, the ketamine scores were -- the mean ketamine score was 90 out of 100 possible points. The median for ketamine was 100. So the ketamine increases were large, robust and statistically significant. In contrast, all REL doses were substantially and significantly lower than ketamine, all doses. That includes the supratherapeutic 6x dose. In fact, all of the REL-1017 doses were statistically equivalent to placebo. No REL dose was significantly greater than placebo, either by mean or median measure. As is typical in these studies, we also measured a variety of secondary measures, and that included overall drug liking, drug high, would you take the drug again and so forth. These findings were all similar to liking in their outcome. We also included an exploratory comparison of REL-1017 versus dextromethorphan, and dextromethorphan was given at 300 milligrams. The results of that comparison were overall similar to those comparing REL to ketamine. That is dextromethorphan produced robust, increased liking and was statistically higher than REL. These findings, I'd like to point out, are also consistent with our animal studies, which show that REL does not engender reinforcing effects in the animal model, and it does not engender physical dependence and withdrawal in the animal models. In conclusion, these findings are also consistent with the 2009 DEA statement on esmethadone, which is as follows: as DEA said, the d-isomer lacks significant respiratory depressant action and addiction liability. So in conclusion, both the oxycodone and the ketamine HAP studies support the conclusion that REL-1017 does not have meaningful abuse potential. Thank you. I'll be happy to take questions, but I will refer to Sergio. So Sergio, take over and let me know what you would like me to answer.

Thank you, Jack. I will. And operator, the data are very clear and kind of, I would say, black and white. But we'll be happy to answer any questions from the audience. Please open the floor for the audience.

[Operator Instructions] We'll go first to Andrew Tsai with Jefferies.

Congrats on the data. I had 2 or 3 questions today. The first one is just on the specific AEs, just wanted to confirm, honestly. It's just like these patients on esmethadone, even at the highest doses, what specific AEs, if any, for these -- maybe these outlier patients? What are they feeling? Can you confirm there is no euphoria, no relaxation, no withdrawal symptoms? I know you said that earlier. But maybe talk about that. And then a secondary question I have to that is my understanding is ketamine, some patients can feel not -- in addition to dissociation hallucination, maybe they can feel euphoria. Is that the case here? And if so, wouldn't that reinforce the viewpoint that esmethadone indeed has like minimal opioid effects?

Thank you, Andrew, for the question. We have Dr. Manfredi and Dr. Pappagallo on the call that -- they run the study. So I will let Paolo, Dr. Manfredi to answer the question. Consider that we just got, very short time ago, the top line. So we won't have all the data. But clearly, if there were some serious or worrisome side effect, it would have been communicated. I will let Paolo to answer the question more in detail.

So to answer the questions about the euphoria, drug liking is the measure that gives you exactly what that euphoria is. And we just heard from Jack that the drug liking was equivalent to placebo. So I would say no euphoria here. And in terms of adverse events of special interest, there might have been some cases of mild dizziness or somnolence, very temporary. So -- but nothing to suggest abuse potential.

Great. And then a follow-up question is a big picture question. I mean, with all these new kind of positive data sets you've generated over the past 6 to 12 months, are there opportunities for you guys to speak to the FDA to, I don't know, gauge what they think about all of these results? I'm just curious because you do have a fast-track designation. And I noticed in the press release that you intend to share the results or submit the results to the FDA. So a little more clarity on that would be helpful.

Yes, sure. Thank you, Andrew. Well, the plan is to discuss with the FDA in a meeting probably happening some time in midyear. And with the goal of being sure that we have done everything that we are supposed to do to show the lack of meaningful abuse potential. And we follow the 2017 FDA guidance by the book, but we want to be sure. Consider that the FDA does not consider top line satisfactory for discussion, so we will have to wait the final report of the ketamine data. We just received the oxycodone final report. And when we have all the package, we'll file with the FDA. And hopefully, they will accept to discuss. And don't expect any indication on a potential scheduling. The scheduling will be up to the DEA. But clearly, the FDA recommendation is very important. So the goal is really just to be sure that we have done everything that satisfy the FDA to show the lack of abuse potential, meaningful abuse potential for REL-1017.

Our next question comes from Yatin Suneja of Guggenheim Partners.

Just a similar question to what Andrew was asking earlier. Is there a mechanism where you can engage with DEA prior to the approval to get their gauge on whether it's IV or V from a scheduling perspective? And can you also just talk about how does it actually work? Like you propose Schedule V for them and then you go back and forth? And then I have one more question.

Yes. Thank you, Yatin. I will -- Jack, answer the second part of the question about how the process works and what we would propose, the Schedule V. In terms of feedback from the FDA or the DEA, it's unlikely they will make any statement before the FDA will give them their advise or their suggestion. We are engaging with the DEA just to be sure that they know us and they become familiar with the data. But we don't expect anything clear on any clear indication before the FDA send -- provide recommendation to the DEA. Jack, would you mind to take the question about the process, how it works and the -- what we will propose, the scheduling of Schedule V and why?

You bet. Yes. And the process actually is much more orderly since the Transparency in Medical Therapies Act went into effect in 2016. And if you'd like more information on that, you can Google the Transparency in Medical Therapies Act. But in a nutshell, what that says is that FDA takes the lead on the scheduling recommendation. DEA has 90 days to finalize the schedule with an interim final recommendation. And since that went into effect, in every case, DEA has met its time line and has provided the same schedule that FDA has recommended. So DEA finalizes it, but they follow FDA's lead, unless DEA has a very good reason for delay or difference, and that has not occurred. In this case, our findings are saying exactly what DEA itself concluded several years ago. So I don't expect any hang-up with DEA. I expect the process to move efficiently as it has over the last 5 years. DEA will be informed of the results ahead of time, so it will not be a surprise to them. The studies from oxycodone, the animals have already been presented publicly and will be presented to DEA and the same with the ketamine study. The ketamine study will also be presented at public meetings. So this is a relatively straightforward process these days.

Got it. And then can you just confirm the formulation that was used in this study for REL-1017? Any different from the ongoing studies? And then can you also tell us the time line or confirm the time line for the upcoming monotherapy readout?

Thank you, Yatin. Yes, formulation is exactly the same that we are using in Phase III. It is the one that will become the commercial formulation is 25 milligrams tablets. And they put -- for the 150, they put 6 tablets in a capsule. So it was double-masking. The timing of the Phase III, the study are enrolling, and we are planning to have data in the second half of the year. A monotherapy probably may come a little earlier than midyear. We'd be more precise in month or 2 when we get more advanced in the enrollment. But the plan is to have data this year.

We'll go next to Joon Lee with Truist Securities.

Congrats on the positive data. Did I hear you correctly about including an exploratory dextromethorphan arm? And what was the rationale for including this? And can -- what are the implications of this result? And I have a follow-up.

Well, thank you, Joon. Yes, we did include dextromethorphan 300 milligrams in the study. And the goal was -- let me give you a little bit of background. So the dextromethorphan comparison is not part of the FDA filing and will not have any impact on the scheduling of the drug. That's why we did not put it in the press release or in the presentation. It's an exploratory endpoint. And that the goal is that we have in development a certain number of derivates of REL-1017 with the same chemical structure but with some change. And since dextromethorphan has a very similar mechanism of action, we wanted to be sure that at least on the likability part, to have some data that we can use. I would not read anything else in the dextromethorphan endpoints, except that we will present detailed data. I believe in June, there is a conference in Minneapolis, the College of Problem with Drug Dependence, where we will present more detailed data. And the good part is that -- as Jack mentioned, is that the REL-1017 is statistically different from dextromethorphan on likability. Dextromethorphan is more likable and it is an over-the-counter drug, so I would leave it like that.

Right, which is really, I think, interesting given that dextromethorphan is not scheduled, right? So okay. For you -- can you...

I want to be clear. It's not going to be part of the FDA discussion or filing regarding the schedule for REL-1017. It was an exploratory endpoint that we wanted to -- for our own scientific and clinical information.

Got it. And then can you confirm whether the FDA was okay with the IV ketamine as a comparator as opposed to oral ketamine at a higher dose? And were there any mechanisms in place to mask the effects of IV infusion?

Yes. So the FDA was clearly okay with the IV ketamine. These are the same protocol and the same dose of ketamine that was used in the Spravato esketamine trial, so the intravenous 5 milligram per kilogram in 40 minutes infusion. That's pretty much the standard of the ketamine comparison, so the FDA wasn't involved with that.

Got it. And one last question. Not to mistake on the data, but when you presented the oxycodone data, the p-values were less than 0.001 across the board. And -- but today, the p-values are less than 0.01. I think they're fine, but just curious if you saw a little bit more variability in the IV ketamine study, HAP study.

Yes. Thank you, Joon. No, we did not. We just did it for simplicity. And since the statistical plan is set for minus 0.05, we just decided to make it simple. But the p-value, they are different ones from another. But the -- I believe most of them, they are below 0.001. [ It was just ] increase in presenting the data.

We'll go next to Marc Goodman, SVB Leerink.

It's Rudy on the line for Marc. Congratulations on the data. Can you remind us what other safety studies are required by the FDA? And what would be the gating factors for filing if you get past your data from the pivotal trials later in the year? And lastly, I have one more question. Can you remind us about the difference between the modified completer population versus the total completers?

Sure. Well, thanks for the question. The -- let me answer first the second question, that is important. The difference between the modified and the full completers. These data are all comers, so it's the full completers. That's what the 2017 guidance states. And then in the oxy trial, we did present the modified completer for the simple reason that we did not have the completer population. We put the data out very quickly, as you can see also for ketamine. But this time, we had statistician to provide both measure. The 2017 guidance look at the all completers. The modified completers is a little bit of an artifact, where the patients that respond to placebo, they are excluded. And there were 1 patient in this study, and there were 3 subjects in the oxycodone study. The modified and the full completers for the ketamine data, they are not -- they're exactly the same. For the oxycodone, there is a difference. There are 3 subjects that responded to placebo. If we include the 3 subjects that responded to placebo, then REL-1017 is statistically equivalent to placebo also in the oxycodone study. I hope I answered your question. We will publish the data as well for the completers in the oxycodone study.

Got it. That's very helpful.

There was another part of your question?

Just asking about what other safety study are required by the FDA? And what are the gating factors for filing?

Yes. So for the 2019 abuse program, we are done. So we'll discuss with the FDA if there is any need to do anything more. But we did in vitro, we did animal and we did the 2 -- we did large human studies. So that's it, unless the FDA wants something additional. In terms of safety study, for filing the NDA, we are not required, as we published last year, to do any 2 years carcinogenicity studies, no QTc interval prolongation study. We are running the standard special population, renal, hepatic, and we don't need to do a food effect study. There is no food effect for REL-1017. So this one will -- they all will be completed before we file the NDA. Probably the last one to be completed will be the open-label, 12-month safety study that is up and running, but it takes 12 months. So that would be the last study. We have a rolling NDA. So that would probably be the last study, part of the rolling NDA. Plan is we'll be more specific later on in the year, but the plan would be to file the NDA sometime in mid-2023.

We will go next to Vamil Divan of Mizuho Securities.

So just 2 sort of follow-up questions. One, going back to the exploratory that you did around dextromethorphan. Can you discuss why you studied against a 300-milligram dose? I'm just curious, why not higher or lower. I just don't know enough to understand why you picked that dose. And then the second question I have, and I think it may have been asked a little before, but just as you look, and I guess this might be more for Jack. But as you look at sort of the maximally tolerated dose, do you just see sort of a trend towards it starting to separate? Obviously, it's still not specifically distinct from placebo. But I'm just curious if there's any concerns. We saw that also with the oxycodone data, where the 150 starts showing a little bit of a trend. And I'm wondering, is that something that Jack thinks could raise any concerns of any kind with DEA or FDA?

Thank you, Vamil. I'll let Paolo to answer the dose of the dextromethorphan, the 300 milligram. There is a specific -- a couple of specific reasons. Paolo will address them.

The dextromethorphan dose is an in-between dose among the doses described by the DEA in a monograph that do have some psychoactive effects. So we did not pick the highest dose, which is above 500. And we did not take the lowest dose, which is around 200. We picked something in between. There was a recent study comparing dextromethorphan with psilocybin. And there, they used 400 milligrams. So we were more conservative than that. We use a bit of a lower dose. And I hope that answers your question.

Yes, I mean, if I can add, the 300 milligram is about 6x the therapeutic dose of a daily therapeutic dose of dextromethorphan as a cough medication. So we try also to match 6x therapeutic dose of REL-1017 versus 6x dextromethorphan. I hope we answered your question. And Jack, would you like to take the second one?

No, I think you summarized it well. The -- it was actually my colleagues at Johns Hopkins who give the 400-milligram comparison with psilocybin. And so the idea is to have a robust positive comparator. And it could have been 400, it could have been higher, it could have been a little lower. But 300 is a -- what I would consider to be a robust comparator and makes a good comparison dose for such a study.

Okay. And Jack, I believe Vamil was also asking about maximum tolerated dose and the effect and the trend in likability?

Yes. The dextromethorphan produced robust significant increase in liking and...

It was REL-1017, not dextromethorphan, was our drug. Vamil, maybe you may want to repeat the question?

Yes. The question was just on the -- when we look at the 3 different doses of 1017, we saw this in the oxycodone trial and now again in this one where there's just a little bit of a trend, maybe almost a dose response in terms of likability as you go from 25 to 75 to 150. I'm just wondering, obviously, it's still not statistically separate from placebo here. It was a little bit -- or was -- I mean the p-value is like 0.08 in the oxycodone trial. I'm just wondering if that may raise any concerns, even though it's still clearly distinct from what we see with the comparator with oxycodone or ketamine. So I'm just curious on that.

Jack?

I could -- Sergio, could you repeat the main part of that question because it was a little quick and light in my headphones.

Yes. I believe Vamil would like to expand and to ask if the maximum tolerated dose of REL-1017, that there is -- it's statistically equivalent to placebo but the score is higher, if you read anything on that. Am I correct, Vamil?

Yes.

Not at all. That's typical. The variability overall for placebo was quite low, as is expected in these sorts of studies. When you go to super high doses, and we call them supratherapeutic. Actually, the 3x is a supratherapeutic dose, there is very little visual increase. There's a little bit more variability at the 6x dose. And remember, that's at a dose that is maximum tolerated. So to put it simply, people can feel something. That doesn't necessarily mean that it's robust liking, and it wasn't not robust liking. But when people can feel something, they often respond with something that we can see. So there are some subjects that had a slightly elevated response. But overall, it is not statistically different from placebo. This is pretty consistent with studies that I've been involved in over the decades.

We'll go next to Jay Olson with Oppenheimer.

Congrats on these results. Can you talk about how these results differentiate REL-1017 from your competitors that do have abuse liability potential? And how do you plan to leverage that differentiation for clinical and commercial advantages?

Right. I believe you're referring to esketamine, that is the only competitor that has -- that is a Schedule III. The scheduling and the abuse potential is only one of the differences. But in this case, you can clearly see that esketamine has a very similar profile than ketamine. So it's speculative, but if we will run the study with esketamine instead of ketamine, probably the result would not be very different from what we have seen with ketamine. So that's one difference, but there are other difference. That includes the hospital and not oral availability. The administration of esketamine in clinic, you have to go to the clinic twice a week for the first month, and you have to stay there for 2 or 3 hours minimum. You cannot drive for 24 hours. So there is several differences and including also the side effect profile. The absence of psychotomimetic effect of REL-1017, it's an important factor. What we do believe we have in common is the efficacy. But everything else, it looks pretty different.

Do you expect that difference to translate into significant clinical and commercial advantages?

Well, we do. We clearly do. It's a once-a-day tablet as tolerated as a placebo, 25 milligrams. And with a comparable, if not superior efficacy that, of course, we will have to prove in Phase III. But based on the Phase II, clearly, the efficacy signal for REL-1017, it's very strong. And we don't expect to have any REMs. And I believe it's public information that in the long-term safety study, it's an outpatient -- the Phase III is all outpatient and in a long-term safety study. Patients go home with 30 tablets in a bottle, and we have no reported issues of anybody trying to take more than a tablet or -- so we feel pretty good. The -- if this data will be -- the Phase II will be confirmed as we hope and expect, in Phase III, the profile is for best-in-class for this new class of drug.

Great. That's helpful. And maybe just to follow up on the dextromethorphan arm. Does that also provide some points of differentiation versus your competitors?

I would say no. Dextromethorphan is a closed chapter. I believe Jack was part of the team that discussed the dextromethorphan non-scheduling and over-the-counter status in the past. Dextromethorphan, yes, the FDA is pretty comfortable with the current status. So we don't -- I know you are referring to AX-05, I believe. And no, I don't think the -- there is any issue with abuse ability or with scheduling for dextromethorphan in the FDA's mind. So no, that's not going to be the differentiation factor, we don't believe.

[Operator Instructions] We will go next to Andrea Tan with Goldman Sachs.

This is Matt on for Andrea. Can you remind us where you stand with discussions with the FDA? And if you have alignment that these 2 studies are sufficient to conclusively answer the question on 1017's abuse potential?

Thank you. Thank you for the question. Yes, we do believe that this is -- complete the old program. We followed the 2017 guidance by the book. So we don't expect to do anything more. We did -- we had in vitro data generated last year. We have animal data that we have presented, and they are very clean. And now we have 2 large human abuse studies. So we do believe it's probably the most extensive abuse potential program that has been run by a company so far. Jack can have more insight into that. But I think we did everything that we are supposed to do.

And I really have nothing to add. We worked closely with the FDA and done everything that they've asked. The data are strong and clear. This is relatively straightforward as scheduling issues go, from my perspective.

And with no other questions holding, I'll turn the conference back to Sergio for any additional or closing comments.

Thank you. I want to thank you all for participating in the conference. And we are always available if there is any further questions. And for now, I wish everyone on the call a wonderful rest of the day. Thank you.

Ladies and gentlemen, that will conclude today's call. We thank you for your participation. You may disconnect at this time.