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spk00: Thank you for standing by. Welcome to the Minerva Neurosciences first quarter 2021 conference call. At this time, all participants are in listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star then one on your telephone keypad. Please be advised that today's conference may be recorded. If you require any further assistance, please press star then zero to reach an operator. I'd now like to hand the conference over to your host today, Mr. William Boney, Vice President of Investor Relations. Please go ahead.
spk08: Good morning, everyone. A press release with the company's first quarter 2021 financial results and business highlights became available at 7.30 a.m. Eastern Time today and can be found on the investor section of our website. Our quarterly report on Form 10-Q was also filed electronically with the SEC this morning and and can be found on the SEC's website at www.sec.gov. Joining me on the call today from Minerva are Dr. Remy Luthringer, Executive Chairman and Chief Executive Officer, and Mr. Jeff Race, Executive Vice President, Chief Financial Officer, and Chief Business Officer. Following our prepared remarks, we will open the call for Q&A. Before we begin, I would like to remind you that today's discussion will include statements about the company's future expectations, plans, and prospects that constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. We caution that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated. These forward-looking statements are based on our current expectations and may differ materially from actual results due to a variety of factors that are more fully detailed under the caption risk factors in our filings with the SEC, including our quarterly report on Form 10-Q for the quarter ended March 31st, 2021, filed with the SEC earlier today. Any forward-looking statements made on this call speak only as of today's date, Wednesday, May 12, 2021, and the company disclaims any obligation to update any of these forward-looking statements to reflect events or circumstances that occur after today's call, except as required by law. I would now like to turn the call over to Remy Lutheringer.
spk01: Thank you, Bill. Thank you so much. So, hello, everybody. I'm really, really very proud and very excited to walk you through these recent results about the open-label extension of our Phase III study. I think these data are really an important additional piece of information concerning rhodoperidone and the treatment of negative symptoms in schizophrenia. But before jumping into the data, I really would like to thank once more all the patients, all the families, all the caregivers, and obviously also the clinical sites here in the U.S. and in Europe who have participated through this trial because I know how difficult it is to be in a trial for more than one year. So let me jump into the data. And what you can see on slide four is But where are the objectives of this open label extension? So the first point, and we discussed this in the past, is to look at long-term safety. And this is to tick the box about one-year administration of the drug, but I think it is also very, very important in order to give us a better understanding of the long-term safety and tolerability of rhodoperidone. As you will see, I think this is very important and extremely encouraging and good for roly-poly. But obviously because, as you know, negative symptoms is the core symptom of the disease of schizophrenia, but it is also the symptoms which are really long-lasting. As you know, negative symptoms are present even before patients have their first episode of positive symptoms and the it is really the chronic part of the disease. So clearly it is very important to continue to follow for longer periods of time what is going on in terms of negative symptoms. So what I will walk you through is through the primary endpoint, which is a modern negative symptom factor score, which is really a validated tool to measure negative symptoms. And afterwards, obviously, it's important to put this in the context of the overall psychopathology of the disease. And I will give you also some key information about what is going on with our drug over this extension of nine months and the overall one-year treatment period in terms of CGIS, in terms of the PAMS total score, and other PAMS items. What is also important, as you know, because keep in mind that, I mean, this study has been carried out in monotherapy, so these patients were only treated, obviously, with Avopirac, with Roliparidone, during the double-blind phase, and neither arm was placebo, but afterwards, during the open-label extension, everybody was in monotherapy, monotherapy of Roliparidone for nine months. So, So this is obviously important to look to relapse rates because this is always something which is important, which is worrisome. And if the relapse rates are under control, I think this is a very, very important and positive attribute to the drug. So clearly, I mean, this is also something I would show you. And all this, negative symptoms improvement, overall psychopathology improvement is significant. uh really important uh if i mean you can demonstrate that i mean this is translating into a functional improvement and i will also walk you through the psp which is the personal social and social performance total score which as you know is our key secondary endpoint in the study and last but not least because now we have generated a lot of efficacy safety data with a drug We have the phase two B study, we have the phase three study. I will try to summarize all this and to integrate all this and to, and obviously I will give you the next steps afterwards. We're kind of going to the next slide, which is slide five. Just a small, how to say, reminder about the study design. So as you can see, after the screening period, the patients, were entering into the double-blind phase for 12 weeks or three months. And we had three treatment arms, 32 mg of our drug, 64 mg, and placebo. And afterwards, I mean, if the patients and the clinical sides were thinking that this makes sense, I mean, the patients were proposed to enter into an extension phase. What is really important to understand here is that these patients are, before they're entering the study, they are treated with, most of them with antipsychotics. They need to be stable over a period of six months in terms of positive symptoms. So in other words, they should not fluctuate too much in terms of positive symptoms. And obviously they need to have a certain level of negative symptoms in order to enter the study. But it's also important to understand, and I'm well aware that, I mean, the Open Label Extension is no longer placebo-controlled, but what we have to be aware, and I think this gives even more value and more weight to this Open Label Extension data, is that the clinical sites, or the PIs, are not aware about the dose that patients are receiving in the Open Label Extension. Neither the patients are aware about the dose they're receiving. The same is true as well for, you know, the patients who were on placebo and are switched to active drug or the patients who stay on active drug. This is definitely completely blinded to the clinical side and to the patient. So, again, this is important to keep in mind because it gives, in my opinion at minimum, more value and more weight to this extension data. So on the bottom of the slide, you have the different parameters. I already went through it, so no need to stay longer on this. So on slide six, I give you the disposition of the open label extension. So you see that, I mean, we started the double-blind phase with 513 patients who were part of the safety population. ITT population is the same number of patients. And what you can see when you're going to the fourth row, you see that a lot of patients from the different arms went into the extension, which is obviously very, very good. I mean, 333 patients went into the extension. And as you can see, it's quite homogeneously distributed among the different treatment arms. When you're looking to the different reasons why some of the patients dropped out, I mean, one of the main reasons is informed consent withdrawal, which is not a surprise because this is a very long study. And for the rest, we will go into the details a little bit later on. But I think a very balanced and very, interestingly enough, I mean, a lot of patients and investigators who have decided that it is worthwhile to enter into an extension. So if I'm going to the next slide, and this is the primary endpoint. This is the modern negative score. So what you can see here, and I did a little bit of explanation, obviously, about the slide, how the slide is presented. So what you can see at the left side of the slide, I mean, I show you the observed data for the three treatment arms of the double-blind phase. In blue, you have placebo. In green, you have 32 milligram. and in red you have 64 milligram. What you can see is obviously that when you are ending this double-blind phase, you can go into the extension, and afterwards, what I'm showing you here on this slide, are all the patients who are receiving 64 in red, and all the patients who are receiving 32 in green. As you can see, at week 52, I mean, the treatment was stopped, and afterwards, I mean, the patients were kept, so you have... an additional measurement point after the treatment has been stopped after 52 weeks of treatment. On the bottom, you have more details, but I mean, I have a summary slide afterwards about all these results. So for the moment, it's not necessary to focus on this aspect. Obviously, as you can see with the green arrow, I mean, an improvement of negative symptoms is a curve going down. And so what you can see, I mean, is that Clearly, when you continue to treat patients, the patients who stay in the study for one year or nine months extension, the negative symptoms, according to the MARTA negative score, continuously improve, and we are reaching levels of improvement which are quite high, and we are at around seven points of improvement in terms of the MARTA negative score. So does this translate into functional improvement? This is on the next slide. Here you have the PSP total score. Again, the only difference here is obviously if you have an improvement in terms of functioning, in terms of everyday life functioning of this patient, which is assessed by the PSP, this is an increase of the curve, yes, and the arrow, the green arrow, is going up. So higher is better. So what we can see again here when you're looking to the double-blind phase, and this is something we already have clearly described when we released the double-blind part of this phase three. This was also the case in our phase two B. 64 milligram seems to do a little bit better job in terms of PSP, in terms of functional improvement, as compared to 32 milligram. But again, when you're looking to the open label extension over nine months, you see that that means this improvement continues and becomes more and more important, which is obviously great news and shows that, I mean, what, I mean, Roliferidone is doing in terms of improving negative symptoms is translating at the end of the day into a functional improvement, which is what you need to see, yes, because... At the end of the day, what is important is, are these patients functioning better? Keep in mind that this is a key secondary endpoint we had in our study. Now, if I move into the next slide, which is slide nine, I just wanted to give you some additional color on all this, on how Roliparidone is doing during the nine-month extension. So on the top left, you have CGIS, and you can see that indeed, in the opinion of the PI or the doctor who is doing the observation, clearly he sees the improvement, which is really good news. When you're going down left, so these are positive symptoms, and according to Marder, and this is really important information. If you remember, we took these patients when they were stable in terms of positive symptoms. So the level of positive symptoms were at around the 14, 15 points, which is obviously a quite low level of positive symptoms. But keep in mind that that means they were on antipsychotics. We switched them to monotherapy of Roliparidone. And what you can see here, interestingly enough, you still have some room left for improvement. But I think Without emphasizing the improvement, I think it is fair to state here that, I mean, positive symptoms at minimum stayed extremely stable. Now, what is interesting, if you're going to the upper part of the slide on the right side, so this is a PANS total score. So this is a complete improvement you can see on the scale. And you see that, again, the total PANS score is improving for the two doses. And it is improving to a very nice level, around 16 points. So what this means is that, I mean, if you consider the improvement we have seen on negative symptoms and the improvement on positive symptoms, this improvement on the total pound scale is obviously related to these two improvements. But, I mean, the general psychopathology is also improving significantly. if you treat your patients long enough in monotherapy with voliparidone. And last but not least, at the bottom right, I mean, I give you the sub-score of the milder negative score, which is emotional expression. And as you know, from the studies which have been done, this part or this sub-part of the milder negative score or this sub-part of negative symptoms at the end of the day is highly common. explaining the functional improvement, or is correlated with the functional improvement. So I think what I try to bring over here on this slide is that all the parameters you consider are improving, and in addition, the improvements you see are technically signaling very nicely that, I mean, on a functional level, the patients are improving. If we go now to the summary table, which is on slide 10, So this gives you the complete information about the parameters I have shown you. So on the right side, the two columns on the right side, these are the results I've shown you on the slides. And afterwards, you see that you have the details in the middle, so two middle columns. These are the patients who received ASA32 or 64 milligram for the complete duration of the trial, so one year. On the left side, the two columns on the left side, so these are the patients who switched from placebo in the double-blind phase to active treatment in the open-label extension. So again, I mean, without going into the details, but I mean, you have noticed in numbers what I presented before, but again, you see that negative scores, PSP functioning, total PAM score, all these parameters are evolving into the right direction here. Now, coming to the very important point that I highlighted at the beginning, which is on the next slide, this is about relapses. So really, I mean, as you know, the definition of relapses is you can find different differences or different definitions of relapses, but I mean, What we took as a definition is really what you can see at the bottom is, you know, patients who dropped out from the study due to schizophrenia symptoms. So this is a definition we have used. And what you can see on this slide, I mean, on the top of the slide, I mean, you have the relapse rate or the number of patients dropping out for schizophrenia in the double-blind part. and at the bottom you have the numbers of patients who dropped out during the open label extension. So when you're looking to the overall relapse rate, which is given at the bottom, we are at around 11.7%, around 12%, which obviously is extremely low, and I am sure that we will get a lot of criticism about this and how is this possible and I will give you at the end my explanation of why this is possible. But I mean what is very clear is that I mean if you treat long enough patients without a drug in monotherapy the relapse rate is extremely controlled and I think this is a take-home message of this slide. Now On the next slide, I mean, this is the safety aspect that we have observed. So I will go through the different points and make some comments because I think they are extremely important to give you a little bit more color on this. But as you can see, I mean, Roliparidone at the two doses, both doses, was extremely safe and well tolerated. And when you're looking to the treatment of emergent adverse events, there were generally mild to moderate, yes, in terms of severity. When you're looking to the, you know, frequently reported treatment emergent adverse events in this 30, 333 patients, excuse me, in doing the open label phase, you see that, I mean, you have 26 patients are reporting headaches. You have obviously schizophrenia worsening, 18 patients, so 5.4%, and you have insomnia in 15 patients. Let me just make here a small comment about insomnia. What we have to keep in mind, even if we are here above one of the mostly reported events Keep in mind that, I mean, it is very well described in the literature about the incidence of insomnia and schizophrenia in patients suffering from schizophrenia, and the incidence is more than 50% in patients suffering from schizophrenia. So, again, even if, I mean, we have some cases of insomnia, we have to put this in the overall context of the disease where, I mean, insomnia is really, really an important parameter or symptom. When you're looking now to the, how to say, number of patients who had a serious adverse event, we have 26 patients who have had a serious adverse event, and five, which is really, I mean, a very low number compared to the number of patients exposed to the drug and the duration of treatment. We have five worm in the PIE. has considered that, I mean, the adverse event was related to the drug. It is worthwhile to mention that one patient died after he has been discontinued from the treatment and is obviously not related to roliparidone, but, I mean, related to respiratory failure. But, again, this patient already was no longer treated with roliparidone. So when you're looking to the number of patients with treatment emergent adverse events, I mean, it is around 11% with 25 patients who had relapses. So this is referring to the slide I presented before. And the rest is a variety of events which are not present. superior or equal to 1% of the patients. So really, I mean, events which are just occurring in one or two patients. Last but not least, in terms of QTC, you see that, I mean, we had really a very limited number of QTC increases. So one patient reached the stopping criteria in the 60 milligram dose. Just to be clear, I mean, this patient, in terms of absolute value, did not go above 500 milliseconds, so he was below 500 milliseconds. But, I mean, why he has been stopped is that one of the stopping criteria is if, I mean, the delta increase is more than 60 milliseconds at the two measurement points separated by 30 minutes. I mean, you have to stop this patient. So this is... why this patient has been stopped in terms of QTC. So, if I'm going to the next slide, how can we summarize all this? I mean, clearly, I think what the open label extension is confirming or giving us as information, and again, I think that this is really very important information is that We have a continuous and really sustained improvement of negative symptoms during the complete duration of the study and during the open-label extension. We have also, as I already mentioned, a continuous improvement of daily functioning, or the patients are really better and they're functioning better. clear information coming out from the PSP. This happens in a context where, I mean, the psychotic slash positive symptoms are stable and where we have really few relapses over one year. And this happens with a drug which is safe and well-colourated. I did not mention, obviously, in the safety part that we did not see any weight gain. We did not see any EPS. We did not see any prolactin increase, and we did not see any sedation. I think we had two patients where sedation was mentioned. So just to give you a flavor of how this looks like. Now, how can we interpret this data? And I think there are There are two interpretations here which are possible and which are the most plausible one. And I think the two interpretations are not exclusive. They are probably working together. But I mean, the first explanation is about the pharmacology of roller paradigm. If you remember, Roliparidone is not directly blocking dopaminergic pathways, and particularly it's not blocking D2 postsynaptic receptor. So clearly we have no direct dopaminergic blocking effect. But what we have here is a molecule which has an antagonistic activity on the serotoninergic 5-HE2A receptor. We have a molecule having as well an effect on the Sigma-2 receptor, also an antagonistic effect. And we have worked a lot to have even more insight in terms of pharmacology over the last year or so. And it is also clear that in addition to these two targets, the molecule has also an Alpha-1a antagonistic activity. So this is really the pharmacological profile. I really would like to emphasize that, I mean, indeed, I mean, this molecule has a 5-HE2A activity, which is important, but, I mean, it has much more because we have this Sigma-2 activity and this Alpha-1 activity. And it is very well described, no more and more, because Sigma-2 is becoming an extremely hot topic in terms of research and in terms of trying to come up with innovative treatments. It is very well known that... Sigma-2 is probably having an impact on glutamate, and particularly on the NMDA pathways, just to give you, how to say, one of the activities you can see when you are working with specific Sigma-2 molecules. So, I think really, I mean, the beauty here is that, I mean, we have a molecule which is safe due to the pharmacological profile, but which is also targeting specifically negative symptoms that has an overall effect on the overall psychopathology. We will, in the future, report more on pharmacology because I think it is important, but I think it is fair to say that probably the pharmacology here is a quite adaptive pharmacology to achieve what we have achieved with goliperidone so far. Another explanation which can explain this data is that You know, when you're improving negative symptoms, and this is extremely well described in the literature, when you're improving negative symptoms, you know, patients are starting to function better. Patients are more adapted to, you know, what is going on around them in terms of family life, in terms if they have a job. So basically, they are much more able to cope with everyday life. And at the end of the day, they are showing improvements in their overall psychopathology. And this is maybe another explanation. So probably the two things are probably synergistic in terms of what we see with the molecule. There is a last explanation, but I mean, I will not emphasize it because we have only preclinical in vitro data. But I mean, this is something we continue to test or to work on. Remember that, I mean, we were able to show that, I mean, when we did rhodoperidone, you can see a very nice increase in BDNF and GDNF. And so you can also raise the hypothesis that maybe we are really helping these patients by doing something in terms of neuroplasticity overall. So really, I think this is the best explanation I see, which is obviously very exciting. And when you integrate this into the, you know, this magic word, totality of evidence, I think this data I just presented over the last 10, 15 minutes are just giving an additional level of evidence that, I mean, rhodioperidone is a drug which is probably helping, at the end of the day, patients to improve in terms of negative symptoms and their overall functioning. Last but not least, before I give over to Jeff for the financial update, what is next? So what is next? We have just recently started the bioequivalent study, this pivotal bioequivalent study in healthy subjects. And as you know, this is one of the activities we have to carry out in order to tick the boxes of the different activities comments, remarks we received from the FDA at our type C meeting from last November. So this is ongoing and obviously when we will have the data in hand we will report on this data. We continue all the other activities which are needed to be integrated in our NDA preparation and we are also putting together all the data, analyzing the data in the right way to go to a pre-NDA meeting as soon as all the different points I'm referencing here are completed. So I think I stop here, and I give over to Jeff for the financial update, and obviously I'm looking forward to hopefully all your questions and interesting questions after Jeff has done his update. Jeff, please.
spk02: Thank you, Remy. Earlier this morning, we issued a press release summarizing our operating results for the first quarter ended March 31st, 2021. A more detailed discussion of our results may be found in our quarterly report on form 10Q filed with the SEC earlier today. Cash, cash equivalents and restricted cash at March 31st, 2021 were approximately $80.2 million compared to $25.5 million as of December 31, 2020. In January 2021, the company received a $60 million cash upfront payment from Royalty Pharma in connection with Royalty Pharma's acquisition of the company's royalty interest in Celtorexant. We also have the potential to receive up to a further $95 million in additional payments contingent on the achievement of certain clinical, regulatory, and commercialization milestones. The significant non-dilutive funding provided by our agreement with Royalty Pharma, both immediate and potentially over the longer term, will support our top priority, the continued development of Roloperidone, our lead asset. Recall that celtorexant is currently in phase three clinical development by Janssen Pharmaceutical, a subsidiary of Johnson & Johnson for the adjunctive treatment of major depressive disorder with insomnia symptoms. We presently expect that the company's existing cash and cash equivalents will be sufficient to meet its anticipated capital requirements for at least the next 12 months from today based on our current operating plan. The assumptions upon which this estimate are based are routinely evaluated and may be subject to change. Research and development expenses were $3.3 million and $8.1 million for the three months ended March 31st, 2021 and 2020 respectively a decrease of approximately $4.8 million. The decrease in R&D expenses was primarily due to lower costs for the Phase III clinical trial of Roliparidone as a result of the completion in May 2020 of the three-month core study portion of this trial. Non-cash stock compensation expense included in R&D expenses was $0.6 million and $0.7 million in for the three months ended March 31st, 2021 and 2020 respectively. G&A expenses were $4.2 million for both the three months ended March 31st, 2021 and 2020. G&A expenses included compensation costs, consulting expenses and insurance premiums. Non-cash stock compensation expense included in G&A expenses was $0.9 million and $1.5 million for the three months ended March 31st, 2021 and 2020, respectively. Net loss was $8.8 million for the first quarter of 2021, or a loss per share of 21 cents, basic and diluted, compared to a net loss of $12.2 million for the first quarter of 2020, or a loss per share of 31 cents, basic and diluted. Now I'd like to turn the call over to the operator for any questions. Operator?
spk00: As a reminder, if you'd like to ask a question at this time, please press the star, then the number one key on your touch-tone telephone. To withdraw your question, press the pound key. Our first question comes from Jason Butler with JMP Securities.
spk04: Hi, thanks for taking the questions, and I really appreciate you going through all the details there. Just thinking about, I guess, both the magnitude and progression of improvement, are there historical data for patients with negative symptoms that kind of speaks to how likely they would be to recover in that manner without treatment intervention, both, again, the magnitude and the progression of the improvement over the full one year? Sure.
spk01: Hi Jason, so great question and obviously I was expecting this kind of question. First I think it's important to mention that maybe the study design we have used is not absolutely the same as what you can find in the literature but nevertheless I mean you can find situations where you have a similar study design and where you can get some some more color, I mean, by comparing our data to existing data. So I think what is very clear is that in most of the cases I have seen, and I mean, we could found in the literature, is that usually, I mean, you have an improvement which is occurring quite fast, and afterwards, the things are really flattening when you are going over several weeks and obviously several months. And so the things are flattening very quickly, yes, I mean, in terms of improvement. I'm speaking here about negative symptoms. If you go with patients who had an acute relapse of positive symptoms, as you know, when you bring them down, they are, how to say, having a small improvement of negative symptoms, which is a pseudo effect, but I mean, after the things are flattening. So basically what it means, I think, is that, I mean, you have no really specific improvement of negative symptoms, whereas in our case, I think it's, with all the precautions of the study design of the open-daily extension, I think it is fair to say that this continuous improvement over time is something which, in the best of my knowledge, to use the term, is unique. Now, in terms of level of decrease, again, I think... We have to put this in the context of the patient population included in this study. Remember that we wanted to have patients who have a minimum score of 20 points in terms of negative symptoms, and they needed to be stable before entering the study. And basically, we ended up with patients who had a score, a baseline of around 20 points. 25, 26 points in terms of negative symptoms. So keep in mind that the minimum is seven points. That's because, I mean, when you're using the pants, there is no zero. One is absence of symptoms on each item. But when you're, what there is a consensus is that, I mean, if you bring back someone to 20 points and below, you know, these patients are probably starting to function again or functioning better, which, by the way, is demonstrated with our PSP data. So I think we are really at the level where, I mean, indeed, you know, based on what is somehow consensus in terms of where you need to be in terms of negative symptoms to be able to function, we are there. So this is, I think, what can be the answer to your question. To compare this to antipsychotics and whatever, I think it's not really what you can do because we are not really dealing with the same pharmacology. We are not dealing exactly with the same drugs here. So, I mean, this is what I can answer to your question.
spk04: That's helpful, Remy. Thanks. And then just regarding next steps with FDA, what would be the trigger for the next FDA interaction? Is it completion of the bioequivalence study? Obviously, we'd expect you to submit a package that also includes this new LLE data, but any sense of, like I said, what the trigger would be for the next meeting and when the next interaction with FDA, formal interaction with FDA could happen?
spk01: Yeah, so I think a formal interaction is a right term because, I mean, we are interacting with the FDA because we interacted with the FDA before we started our bioequivalent study, because we sent them the protocol. We also have already answered some of the questions which came out from the Type C meeting. But it is, I think, extremely clear that one important point or box to tick is about the the bioequivalence between the formulation, which has been used in Phase 2b and Phase 3. And when this study is completed, indeed, we will really start to finalize all what we need in terms of briefing book documentation in order to go back again to the FDA to discuss next step and NDAs. But yeah, so this is the timing of the sequence of events which will happen before we go again in front of the FDA.
spk04: Okay, great. Thank you, and thanks for taking the questions. Thank you, Jason.
spk00: Our next question comes from Tom Schrader with BTIG.
spk06: Good morning. Congratulations on the data and also on the perseverance. It's really remarkable, especially in the face of a second pretty good drug. So my question has to do with your final points you hit on that are, I think, quite interesting, this idea that the drug gets patients to a good enough state in terms of negative symptoms that then they're able to form routines and sort of get going on life again, and so you have this long-term effect. Do you need to sort out the role of the clinical trial environment in that? Do you think you need to do a year of placebo-controlled now, and is that hard? And then the follow-up is, do you think the continued improvement in positive symptoms argues that it is a pharmacologic effect? So I'd just like to hear your thoughts on that idea.
spk01: Yeah. So I honestly, I mean, you know my opinion. I mean, I think when you're going according to the guidance of end of 2019, if you're dealing with an unmet medical need and the If you have really, I mean, the package we have today, I think we have enough data to go to see the agency again. And obviously, we are really listening to all the different comments we are receiving. Do we need a study where we are doing a one-year placebo control? Is it possible? I think it is possible to run a study like this. I think, obviously, that it will give additional color about how meaningful all this is we have here. But nevertheless, keep in mind that there is some blinding in this data, nevertheless, and historical comparison are really speaking in favor of other data. But if we have to do such kind of study, and I think it is an important study, I think that, I mean, because we are here facing such an end of medical need, this should be a study which has to be done in phase four. And there are much more other studies which could be done in phase four to show the full potential of the drug. Not concerning the pharmacology point you're raising, obviously, to be very honest, when I started, and this is not a long time ago, to work on this molecule, I was convinced that the pharmacology is the right pharmacology to you know, to keep positive symptoms stable or to improve them. A long time ago when I was very young, I mean, I was the first one working on MDL-109-07, which is a pure 5-H2A antagonist. And, you know, the history or the story of this molecule, it was stopped because it was not better than haloperidol in terms of controlling positive symptoms. But it is completely clear that a 5-HE2A antagonist is able to do something on positive symptoms. I'm not saying that, I mean, a 5-HE2A antagonist is able to control an acute episode of positive symptoms, but here we have, I think, good drugs for acute episodes, which are the antipsychotic system and other beta-blocking molecules, but definitely there is something going on. There is also, interestingly enough, good literature out there showing that, I mean, for younger patients, whereas a disease is really not already chronic, a treatment with a 5-HE2A alpha-1A molecule is probably better than going to treat them with a D2 blocking molecule. So there is quite convincing literature out there. So again, I mean, this is an additional layer telling us that, I mean, you're improving negative symptoms, positive symptoms, excuse me. And last but not least, if you're going back to the history of Sigma, I mean, there were two Sigma ligands in development a long time ago, and I was involved in one, which was a Sigma molecule from Sanofi I tested in my research institute when I was running my research institute. And the hypothesis there is that, I mean, Sigma is modulating the dopaminergic tone, yeah? And as you know, schizophrenia is not about only hyper dopaminergic activity, it's also about hypodopaminergic activity, particularly in the prefrontal areas of the brain, which might also be linked to negative symptoms. So yeah, I agree with you. I think the pharmacology is definitely contributing here.
spk06: If I can just ask a quick follow-up, was the removal of drugs for positive symptoms for the entire OLE, was that a complexity, or were these patients that were essentially so sure those drugs weren't working for them that it was not an issue with treaters?
spk01: I think it was no longer an issue because we had already the data from the phase 2b. Keep in mind that in the phase 2b, we had the a six-month extension to the 12-week double-blind. So I think, you know, going to the ethical committees and so on at the beginning, I mean, at the beginning of the project, I mean, speaking here about the Phase 2A, yes, I mean, it was obviously a challenge because everybody believed, I modestly think that our data are triggering a lot of research about the what you should do to really help these patients and to keep them, obviously, stable in terms of positive symptoms, avoiding relapses and so on. So a lot is going on. So I think we already had good data indicating that the risk is not really important. Keep also in mind that if, I mean, you... you ever have worked in psychotic facilities, you know, a patient becomes not, how to say, active in terms of positive symptoms and has not an acute relapse, even if we call this acute in one hour, yes, I mean, this is a process which is going on for several days or several weeks before, I mean, the relapse occurs or the necessity of hospitalization is there, yes, and And in bracket, this is the reason why I mentioned also the insomnia part, because, I mean, often some of the symptoms are, for example, obviously more agitation, a little bit more aggressivity, but also definitely insomnia. So, again, I think skilled investigators are really aware about this, and they have the tools in order to pick up someone who might relapse, basically, at the end of the day.
spk06: Great. Thank you very much for all the details and congratulations again.
spk01: Thank you so much.
spk00: Our next question comes from Jay Olson with Oppenheimer.
spk07: Oh, great. Congrats on these new data and thanks for taking the questions. Can you talk about the performance of the patients in the open label extension who switched from placebo to active and how those patients compared to the patients who were on active all along and what you might have learned from that comparison?
spk01: Yeah, so this is really a great question. And I think the answer is on slide 10, yes, I mean, on the summary table. So basically, I think the best interpretation I see of this data, obviously, the patients who completed the double-blind phase resealing placebo, let me call them placebo responders. I mean, but what you can see when you're looking to comparing, you know, the different, you know, groups here, you know, and comparing particularly the patients who have been treated for the complete duration of the study with active drug versus the one who switched to active drug after the double-blind phase. I think what What is added to these patients in terms of improvement is the improvement in terms of the specific aspect of negative symptoms which is related to functioning, which is this emotional experience. You see that the PSP is really picking up. So basically, I think what we are doing here when we are putting our drug on board, even to patients who have response to placebo is that I mean you are really improving them specifically in terms of negative symptoms in terms of functioning so this needs a more detailed analysis but I mean this is what is popping up when you are really trying to integrate the data here but clearly I mean they are improving and best of what I can see from the data as of today is that I mean they are just having the additional boost here in terms of specific effects in terms of negative symptoms and functioning.
spk07: Okay, great. Thank you for that. And then maybe if you could talk about from a big picture perspective, why has it been so difficult to develop drugs to treat the negative symptoms of schizophrenia? And then from a competitive perspective, maybe if you could compare Roloperidone to Pima Vance are in in terms of the mechanism and the data that you have or any other drugs in development for negative symptoms. Thank you.
spk01: It's a great question and I should not be too long, yes, because here I could go on forever, yes, but I think we have to recognize that schizophrenia is basically about negative symptoms and this is the most enduring symptom or set of symptoms you have in the disease present in adolescence before they have really the full-blown disease and extremely chronic over time. So really to target this aspect needs to have a drug when you definitely are targeting the right pathways in the brain, I think. It's clear that, I mean, and this is my dream that post-approval we will do some studies where we are going really to adolescents or to patients at risk or to first episode patients because, I mean, there I think the likelihood to have these patients is even bigger. So what I also think is that, you know, and don't take me wrong, antipsychotics or, in other words, dopamine-blocking molecules are important molecules But these are major tranquilizers, and they were developed as major tranquilizers to treat really the acute path of the disease. And it is good to see that we know we have some treatments, even blocking dopamine, who are less sedating, less impairing, and also less impairing in terms of negative symptoms. So also data showing that when you're lowering the antipsychotics exporter, you see also the patients functioning a little bit better. So I think this is the most difficult part to treat. Keep also in mind that I mean negative symptoms is a construct because you have, you know, you have abolition, you have anhedonia, you have all these kinds of things. I personally think that you need to have an effect on abolition. Why? When you think about these patients, they were really good at school, they were interested in a lot of things, and suddenly, they are losing this capacity to be interested in something, and this is the beginning of all the symptoms you might see afterwards in the disease. I really think that, I mean, what our data are showing is that, I mean, we are improving abolition, and afterwards, you know, you have this positive loop starting. So again, long story short, I think you need to have a drug which is not impairing. You need to have a drug which is doing the right job in terms of targeting the right pathways in the brain which are involved in negative symptoms. And afterwards, I think the patient has insight with the help of a caregiver and people at the hospitals, a psychologist. I mean, they... slowly but surely are coming back and are able to cope with the everyday life. So this is a reason why. Comparing to competition or whatever the term is, I'm hesitating to do this, but you heard me already saying that I think the 5-HE2A activity is an important activity if you want to really treat the overall psychopathology and particularly positive symptoms. Keep in mind also that the 5-HE2A molecule is also having an effect on sleep, which can be related to memory consolidation, cognition. But honestly, I think it is not completely enough in order to have really a complete recovery and a patient who is functioning at the end of the day. So again, I think So this is a reason why. And I think I should stop here compared to this comparison to competition because it would not be fair to my colleagues who are trying to come up with these other innovative treatments.
spk07: Great. Thank you very much. That's super helpful. I appreciate you taking the questions. Thank you.
spk00: Our next question comes from Douglas L. with HC Wainwright.
spk03: Hi, good afternoon, or good morning. Thanks for taking the questions. Just, you know, I think after we saw the data from the placebo-controlled portion of the study, you sort of indicated that really we're going to sort of focus in on the 64-milligram dose. Just given what we saw from the open-label extension and just sort of really the robustness of what we saw with 32-milligram, and I know it was sort of seems very manageable. We did see some QG prolongation. Does that sort of make you think or sort of increase the reason for pushing development with a 32 milligram as well, just to have that as a therapeutic option?
spk01: So, you know, we discussed this, and I'm really in favor always of having different doses, you know, as an option for the treating clinician. Yes, I mean... experience shows that, I mean, this is very helpful. This said, I mean, when you're looking to the data, I think, yes, I mean, it's a fair statement to say that the two doses are showing very, very, very similar effects. But what it is also, I think, why it is also fair to say is that 64 seems to do a better job in terms of functional improvement. I mean, it's quite clear that, I mean, In terms of PSP, 64 is doing a better job. I'm not saying that 32 is not doing anything. It's definitely improving patients, but 64 seems to be better. And, you know, we do not experience sedation. We have no EPS, nothing like this. So probably, I mean, 64 is probably a better dose in order to really help patients at minimum at the beginning of treatment. So long story short, I think if we could convince the FDA that the two doses are helpful, maybe 32 as a maintenance dose and 64 as a dose where you can help patients at the initiation of treatment or even when needed during the course of treatment, I think this would be great news. Keep also in mind that 32 is a dose we will continue to work on because post-approval we will have to do the pediatric studies, and for the pediatric studies, 32 mg is one dose we are considering. So we will accumulate data also with 32 mg, but I agree with you. I think the two doses are helpful. Even so, I think 64 is a little bit more effective in terms of improving functioning.
spk03: And, Remy, just as a follow-up on the dose thing, You know, in talking to clinicians, and clearly I think you've demonstrated that this drug can have significant utility as monotherapy. You know, in just talking to some clinicians, many sort of talk about this as being used in combination with another antipsychotic. And do you think in that context, perhaps the 32 milligram might be the way to go? Or do you think even there you would prefer the 64? And I have one other quick follow-up after this.
spk01: It's a great question. I think what this data will generate is a lot of discussion about do we need in all the patients a chronic treatment of antipsychotics. So this is already a more broader question going largely beyond the Minerva. But I think really that we could think about a strategy to treat patients while in a 32 milligram would be the maintenance dose and you have an ASER 64 milligram or an antipsychotic to help going over the hump of an acute episode of agitation, some more predominant positive symptoms. And I mean, this might be the way to move forward. So this is how I see it. So probably, I mean, this opens the space of a lot of different strategies for a larger number of patients suffering from schizophrenia.
spk03: Okay, and then just, I know, you know, we're certainly, and the strength of the data certainly would suggest, you know, you have an approvable drug. Just in the, if the agency were to sort of still request an additional phase three, just given what we saw from the open label, sort of maybe building on sort of what Tom's question about how you seem to have, you know, as time goes on, the benefits seem to accrue. I mean, would there be worthwhile reconsidering sort of having a longer term double-blind placebo-controlled section. I mean, I know it sort of reduces some of the comparability, but just clearly it sounds like, it looks like the effects continue to build over time, and presumably that would, a longer study would sort of mitigate some of the waxing and waning on the placebo arm as well. Thank you.
spk01: It's a great question, Doug. You know, just, I mean, if you're looking to the data, remember, I mean, we had the p-value four weeks and eight weeks in placebo compared to 64 in this trial. It's a double-blind phase, and we had, obviously, a significant difference in the phase-to-B study, even at week 12. Keep also in mind that in the modified ITT population, we had a nominal p-value of 64. So I think, really, we have really suffered about the fact that, I mean, we had an extremely positive phase-to-B study, and because of a drug is not cannot be picked up, excuse me, due to side effects. I mean, we suffered a little bit from the placebo inflation, yes, I mean, over the double-blind phase. All this said, I mean, Doug, I agree with you. I think longer is better in order to get the placebo effect under control. So I'm not saying that we should do a longer study. I'm just saying that it is something to consider. If, I mean, we think about the next trials, whatever type of trials, we'll be driving.
spk03: Okay, great. Thank you so much, and congrats on the open-label data. Thank you, Doug.
spk00: Our next question comes from Miles Minter with William Blair.
spk05: Hi, everyone. Congrats on the data, and thanks for taking the questions. That 11.7% relapse rate seems pretty impressive and definitely above the expectations of clinicians that i've talked to on on roller paradigm monotherapy here um you know a brief look at literature would suggest that at least in acute psychosis patients there's as high as like 40 to 80 percent relapse over 12 months when you withdraw therapy i know this is a completely different patient population so like how do we think about that 11.7 percent relative to what we would expect in the real world with this particular patient population in the phase three?
spk01: Yeah, great question. So obviously, I mean, when you're in a clinical trial, I mean, there is always something which is not absolutely the same as in real world and when you're in your clinical practice. As you said, I mean, we tried really to to go according to clinical practices. I mean, so in other words, we switch quite quickly from the antipsychotic to our drug in monotherapy. And all this is very similar to what you're doing in clinical practices. So I think it can be compared to what will happen in real life. Now, your question about this specific study population, I am not with you here in terms of specific studies. study population. I mean, I think we just took the patients at a different level than what you're doing usually in acutely relapsed patients. So basically, you know, when we're looking to our inclusion-exclusion criteria, they are very similar to what you have in other trials. Yes, indeed, I mean, we don't have the criteria of the total PAMS score. We have the criteria of checking that, I mean, these patients have a certain level of negative symptoms. And indeed, we are switching them from antipsychotic to our treatment when they are stable in terms of positive symptoms. And it's fair to say that the positive symptoms, 14, 15 points is quite low. That's why I look completely with you that this is a different patient population. And when you're going according to the literature based on our research, eligibility criteria and this represents around 60 to 65 percent of the of the patients with a diagnostic of schizophrenia so so again I mean it needs to to be fine-tuned I'm not claiming again that I mean our drug is a data we have currently in hand is a drug which helps to treat acute episodes of positive symptoms not at all I'm not saying this but uh I'm not completely with you that this is a completely different population than the population we are currently seeing in clinical trials and the population we have to treat in our clinical practice. So this is my answer to your question.
spk05: Yep, no, completely understood. And the relapse rate regardless is definitely impressive. Maybe one on the bioequivalence study as well. I know there was a mention in the press release this morning that you'd be testing an additional... commercial and scalable formulation or at least one of them. Is the aim in this trial still to determine non-inferiority between the phase 2B, the phase 3 and these commercial formulations in terms of area under the curve exposure? Are we going to be looking at that BFB520 metabolite again that I know was the sort of concern with the QTC wave prolongations at the phase 2? Any thoughts that would be helpful?
spk01: No, no, I mean, you completely described it correctly. I mean, definitely, remember, we know that the efficacy is driven by exposure, because we did a lot of PKPD modeling, and obviously, we will do this with the data, including the extension data. So this is a primary objective, for sure. And we will continue to control the metabolite and BFB520 in particular. So you completely described what is the objective of the study.
spk05: Okay. And the final one is just for Jeff. You mentioned 95 million in potential milestones from the seltzer exant royalty sale to royalty pharma. Some of those link to clinical milestones. There's a lot of phase three trials going on at Janssen for that product. Can you comment whether any of those milestones are weighted to like the readout of one of those trials? Does the whole program have to be completed before you would potentially receive a milestone there? Anything you can disclose there would be great.
spk02: Yeah, so there's a mixture of triggers. Part of it is due to clinical progress. A significant part of it is due to regulatory approval in different geographies. and there's some sales bonuses there as well.
spk05: Okay, cool. Thanks for the questions, and congrats on the data. Looks great.
spk00: Thank you.
spk02: Thanks, Myles.
spk00: That concludes today's question and answer session. I'd like to turn the call back to Remy for closing remarks.
spk01: Yeah, thank you. So thank you all, and hopefully you enjoyed it. I think... We continue to work hard to put together the best package here because I think it is extremely motivating the data we have seen today and I think it is also extremely important that this drug is moving towards patients who are in need of new treatments for negative symptoms because keep in mind that there is no treatment approved as of today in the US for negative symptoms. I'm really looking forward to update you very soon about the bioequivalent study, about pharmacology, about all news coming up. Thank you again, and hope to speak with you very soon. Bye. Have a nice day.
spk00: This concludes today's conference call. Thank you for participating. You may now disconnect.
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