Minerva Neurosciences, Inc

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.

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.

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.