Ladies and gentlemen, welcome to the evenamide TRS Study 014/015 six-month results conference call. I am Sandra, the conference call operator. I would like to remind you that all participants will be in listen-only mode and the conference is being recorded. The presentation will be followed by a Q&A session. You can register for questions at any time by pressing star and one on your telephone. For operator assistance, please press star and zero. The conference must not be recorded for publication or broadcast. At this time, it's my pleasure to hand over to Stefan Weber, CEO of Newron. Please go ahead, sir. Happy New Year to everybody, welcome everybody to this call by Newron's team. Thanks for your patience for a few minutes so we could allow everybody to join who was dialing in. With me today is Ravi Anand, our chief medical officer, who will join me in the presentation, and the Vice President Commercial Affairs from Morristown. Good morning, Dennis. Dennis Dionne, who will join us for the Q&A session. This call is all to present to you the absolutely overwhelming safety and efficacy results from the first 100 patients suffering from treatment-resistant schizophrenia, no longer benefiting from their current or any other available antipsychotic, who were randomized to our Studies 14 and 15 and got evenamide as an add-on treatment to whatever current medication they were taking. We are today looking at the six months results. You might remember that we did review the six weeks results in June last year. At that time, we already had very promising and encouraging outcome. We might have hoped at that time that we might be able to maintain the level of benefits. What we will show to you today is absolutely striking outcome, clean safety, and statistically significant improvement of all the patients with all the endpoints, and a substantial improvement over the results we had seen after six weeks. We indeed believe that these results could turn into the most promising, the best news for TRS patients since clozapine was approved, the only approved drug ever in the late '80s of the last century. Before we get there, please allow me, for those who are new to the story, a few minutes of an overview on Newron before I hand over to Ravi Anand. I assume you have all been able to download or access the slide deck that was connected to the press release of this morning. I'm going to that slide deck now. Slide one. Newron is all about developing and getting approved innovative treatments to improve the quality of life of patients suffering from CNS diseases. This magic machine, which is so brilliant until it fails us in diseases like Parkinson's, Alzheimer's, or schizophrenia. Newron is a very small team headquartered in Milan, Italy, with a subsidiary in Morristown, New Jersey, where we have our commercial operations, CMC, and part of our R&D team. We are listed on the Swiss Stock Exchange since 2006, our shares can also be traded at the Dusseldorf Stock Exchange, et cetera. Please read the disclaimer on Slide two carefully. We move on to Slide three, which is the highlights of the company. We have already brought a first drug to the market, Xadago, an add-on treatment in Parkinson's Disease. That compound we took on when it was in early preclinical stages when the company was created. We have taken that compound onto the market in the European Union. It was the first newly approved new chemical entity in more than a decade in the European Union, and we brought it to the market in the United States, where again, it was the first NCE approved in more than a decade in 2017. This drug is licensed globally, and it has paid more than EUR 70 million of down payments, milestones, and royalties to us. It comes with a long patent life until 2029 in Europe and 2031 in the United States. For whatever, it is good, take it as a proof that we know how to take CNS drugs to the market to overcome all the development hurdles and the regulatory hurdles as well. evenamide now is the real value driver for our shareholders because this drug does not only offer a new mechanism of action, but also a completely new positioning in schizophrenia. We are permanently looking for additional assets that fit our strategic criteria to broaden our pipeline. We have material news flow to come from evenamide, and you'll see that in a few minutes. The management team has taken drugs to the market before, and as you just heard, also from Newron. We are right now able to dispose of EUR 40 million for the next one and a half to two years, which takes us well into 2024 and allows us to reach all the value inflection points of the ongoing studies. If we move to Slide 4, this is the pipeline of three compounds. I just want to show it to you to mention one thing. These compounds all come from the same class of compounds. They have one mechanism in common, which clearly sets them apart of everything else that is on the market in those indications. They all have a mechanism that affects, modulates glutamate in the brain. Only the excessive glutamate, leaving the basal glutamate intact. This is driven by a voltage-gated sodium channel blockade. That is why these compounds are unique in Parkinson's, where they do not only improve Parkinsonism, but Xadago also reduces dyskinesia, the most common side effect due to levodopa therapy today. That is why evenamide is one of its own in schizophrenia, and that is why ralfinamide is one of its own in certain types of pain. Let's focus now on evenamide and how it is differentiated in schizophrenia. No need to mention that schizophrenia is a huge market. We are talking about 1% of the global population, wherever you go. We're talking about more than 30 compounds not showing sufficient and sustained benefit for the patients. There's a huge need for a compound with a new mechanism of action and positioning, just like evenamide. evenamide would indeed qualify to become the first add-on drug ever in schizophrenia. We can change non-responders into responders. There's no need, given this as an add-on therapy, to change the current therapy, which reduces the risk of relapses, hospitalization, and suicide. It's ease of use for patients and physicians. This could, and now coming to the treatment-resistant part of schizophrenia, become the first and only treatment-resistant drug or treatment since and beyond clozapine. Of the total schizophrenia population, between 30%-50% will, from the very beginning, be treatment resistant or become treatment resistant over the years. The only therapy approved for TRS is clozapine. This would be the first drug since clozapine. Within TRS, it is our aim to keep a small niche indication of those patients who are treatment resistant to clozapine in the United States. That is about $200 million of annual business, and that is something that we could commercially manage. What do we have to show to you? We do already have positive results from a phase II study in non-TRS patients, the first indication. Based on those positive results, we started the first of two pivotal studies in non-TRS. The study's ongoing and recruiting patients and should produce results still this year. Now we are looking at the pilot study in TRS patients, which is ongoing. Four-week results have already been presented in June, and six-month results are presented right now. We will then come back to you with 12-month results in the months to come. This is indeed the first study in patients suffering from TRS. Given the outcome we have seen after six weeks and six months, we have decided that we will start the first pivotal study in TRS still this year. We would have one pivotal study in non-TRS, one pivotal study in TRS. That is it to file for approval. This compound offers the chance for early market access. It comes with a long exclusivity left, 2033 from the composition of matter and beyond in the European Union, where we are benefiting from the 10 years exclusivity post-approval. At all that, let me hand over to Ravi to start with slide six. Thank you, Stefan. Good morning and good afternoon to folks attending from the U.S. I think Stefan has laid the grounds basically for schizophrenia. I don't need to go into great detail except to once again remind folks that schizophrenia is a disease which has been known to mankind for a very long time. Virtually all of the attempts to develop a treatment have been more or less following the similar mechanistic story. We have probably over 30 unique antipsychotics on the market. They all seem to work in short-term treatment. They do control positive symptoms for some period of the time, overall, their efficacy begins to fade. These compounds, whether they are first generation or second generation, sometimes called as typical and atypical, do not seem to have an impact on negative symptoms, cognition, or functioning. The reasons why we have seemed to be following the same pathway is that we always believe that because the first drugs, like chlorpromazine and Haldol, block dopamine receptors, this must be the mechanism. All developments have tried to model that. The atypical ones realize that having too much dopamine blockade leads to significant motor side effects. Serotonergic antagonism was introduced to offset some of the EPS findings. They produce problems of their own, such as sexual dysfunctions, weight gain, et cetera. What we realized, I think, or the field realized in the last 20, 30 years, mainly due to the advent of advanced technologies like MRS spectroscopy, positron emission tomography, that actually the causal findings or the earliest findings in patients who were not yet having the first episode of schizophrenia, but were in their teens and the prodromal symptoms, was that there was an excessive release of glutamate. This glutamate release precipitated the symptoms of schizophrenia. Since that time, there has been a significant effort to try to figure out how to use this in therapy. To this date, all of this has failed. In schizophrenia, we also recognize there are patients who are going to be treatment resistant right from the beginning. Right in their first episode, they do not respond to antipsychotics. These patients, in their brains, have high levels of glutamate, but normal levels of dopamine. There are patients who respond to antipsychotics. These are patients who have higher levels of dopamine, but normal levels of glutamate. There are those patients who start off by responding, but within a few years, stop responding. It seems to be there is a continuum among a subgroup of patients with psychosis where they become increasingly resistant to the effects of therapy. There have been many definitions of treatment resistance. The latest one comes from the TRRIP Committee, what they defined is basically that you have classes of patients who may have inadequate response but not meet the criteria for resistance. We think generally there are about 40% of patients with psychosis or schizophrenia who, within a few years of treatment, are in this category. These will be classically the kind of patients who are entered in the CATIE study. Five to 10 years of disease, switching from one antipsychotic to the other, but not getting adequate relief. There are 30% of patients who are the real treatment-resistant schizophrenia. As I've said, there's a continuum, and the 30% could blend into 50% in one categorization, could shrink to 20% in another categorization. The issue with schizophrenia is that it's not just the positive symptoms which are occurring, like delusions, hallucinations, which disturb everybody. The fact that this occurs, the first episode in males is around the age of 20 or below 20, and in the females, about five years later, which means the patient's educational efforts, ability to function in society, the ability to live at home, all of these are compromised. No drug to this date, including clozapine, has been able to eliminate these symptoms, reduce the progression of the disease, reduce the disability. What is also known in schizophrenia is that there is a high incidence of suicides, high prevalence of suicidality. About 13% of patients with schizophrenia die of suicide, and 50% actually attempt suicide. This is despite the fact these patients are on antipsychotics. Therefore, we have chosen the pathway that basically what we would like to do is to target a different mechanism with evenamide. Moving on to the next slide, which is slide seven. Clearly, schizophrenia is a very large market. Currently, with the fact that most of the drugs are generic, is still crossing EUR 20 billion and growing. What we do not have at the present moment is a single antipsychotic that can be used as an add-on therapy for patients who are inadequate responders or treatment resistant. One of the indications that we are looking for evenamide, will be as an add-on therapy to any existing antipsychotic, whether it be first generation, second generation. In other words, could be dopamine antagonist or a dopamine serotonergic antagonism. Some of the data that I will describe to you shows that the benefits of evenamide do not depend upon what the inherent mechanism of the underlying antipsychotic was. In other words, it could work with anything. The inadequate responding patient population, as I mentioned before, could be as much as 70% of patients with schizophrenia. We know from the CATIE study that these patients are unlikely to benefit significantly from any antipsychotic, and switching from one to the other in the CATIE study, part 2, did not confer any greater benefit. This could be a very large population. The second population, which I think we are inherently interested in, is the TRS population. There are follow-up studies done by the Institute of Psychiatry, which show that in patients with TRS followed up for 10 years or more, there are glutamatergic abnormalities, but not dopaminergic abnormalities. That is basically what we would like to target. If we are able to be successful in demonstrating a benefit in TRS patients, this would be not only a benefit for patients, for physicians, for the management of patients with schizophrenia everywhere, but also inherently will lead to a very strong Health Technology Assessment to support coverage of the drug in the marketplace. In treatment resistance, of course, as Stefan has mentioned, clozapine is the only drug that has been approved, and that seems to work in about 30% of the patients. What is not generally recognized is among the 30% of the patients who are put on clozapine, about 30% do not respond. For these patients, there is no other treatment available. It is shotgun therapy, but there is no real mechanistic way of dealing with these patients. In the U.S., it's estimated that this is about probably less than 200,000 patients, which will probably shrink down to about 50,000, 60,000 patients who could be managed. These are generally distributed in the VA hospitals, in the large public institutions, and they could be easily managed by a small company. Moving on to the next slide. How did we decide that evenamide is a drug for schizophrenia? On slide eight, you'll see that there are a lot of models listed. We generally believe, and the field believes now, that schizophrenia is not really a behavioral disorder, but it's actually an information processing deficit. The average schizophrenic patient is unable to process information which is coming in from multiple sources and to be able to deal with it. These inputs lead to false assumptions, false conclusions, and therefore, the patient, in a way, is actually reacting to the stimuli, but not in the way that you and I would react to. We have concentrated most of our efforts on information processing deficits. As you can see, we've looked at negative symptoms, positive symptoms, psychosis, mania, cognitive impairment, impulse control, mood symptoms. We have tested evenamide both as monotherapy and as add-on therapy. We have chosen at this moment to go with add-on therapy. The two reasons why, I think, first of all, in add-on therapy, the dosage required to produce a response is lower. This reduces the possibility that evenamide might be adding to any adverse events in these patients. The second is that the treatments we are currently given are not entirely useless. They do control positive symptoms to some extent. By adding on to those, what we intend to do is to take these patients who are no longer responding to their current medication, and in a way, like ECT, jolt the system to make sure that the excessive glutamate release is inhibited, and they can start responding to it again. At some point, it may be possible that we may also go in for monotherapy. The next question, of course, then is basically how does evenamide work? Evenamide works through a unique mechanism. It's the only drug that we know that is working in the CNS space, which does not interact with any receptor of the 130 that are currently believed to be associated with CNS actions. Evenamide is only inhibiting sodium channels. It's not selective for any single subtype, but it affects all subtypes of sodium channel blockers or sodium channels. The important finding is that it affects them in a way that there is no interaction on any other organ system. Mechanistic studies done with evenamide indicate that it is acting through two separate mechanisms. In the last graph that you can see, there is an experiment which is describing the, Ravi? Ladies and gentlemen, please hold the line. We lost connection with the speakers. Okay. Sandra, will I be online? Yes, sir. You are online. I will inform you as soon as Ravi is connected back, okay? Yes. Let me go on until Ravi is back. We are looking at slide eight, that is the mechanism of action. As Ravi has just mentioned, we are looking at the voltage-gated sodium channel blockade. You see in the left part of the graph that this drug is only acting when it is required. In the middle chart, you see that it will only apply to those nerve cells that are excessively firing, and we leave those nerve cells intact which are normally firing. Hi. I'm back, Stefan. Thank you, Ravi. I'm just on slide eight. Yeah. We are looking now at the inhibition of glutamate release. Yeah Now with the veratridine model. If you can go on there, then we can go on with slide 10. Okay. First of all, as Stefan may have pointed out, basically, as you can see from the first part of the panel, this is a very smart drug. When the neuron is firing normally, you can see that the amount of medication needed to block it is 25 micromolar. When it's not firing normally, it's inactive, then you only need 0.4 micromolar. This is exemplified in the middle one, where you see 2 categories of neuron firing, high frequency and low frequency. High frequency is what we see when we have epilepsy and conditions of this type, and in schizophrenia, where you have burst firing. Here, one micromolar concentration completely wipes out all the abnormal firing. Low-frequency neuron firing, which is necessary for our functioning. If that gets blocked, you get significant side effects like with carbamazepine. You can see that one micromolar has no effect at all. How does this happen, this voltage gating? If you can look at the right side, the microdialysis model. This is in vivo microdialysis. There is a way of measuring the glutamate level in the brain. As you can see, the flat part of the curve, this is the very beginning. There it's very flat, so the basal glutamate levels do not change with evenamide. We inject veratridine, which is a sodium channel pore opener. Glutamate flushes out, which is a black peak. You can see that evenamide reduces this peak dose-dependently in the blue and the red colors. This is the only mechanism by which this drug is acting. Now, based upon these data, we had discussions with regulatory authorities, we initiated a phase II study in the U.S., a placebo-controlled study in non-TRS patients, which is in slide 12. In this study, what we were able to show, that in a small group of patients who were on risperidone and aripiprazole and not responding well, the addition of evenamide improved symptoms, positive symptoms. The clinical global impression of change done by a psychiatrist with all scales showing a benefit for treatment. This was the stage at which we decided basically that we have enough data to be able to go into the next category of things. Basically, what we had was regulatory interactions, which are shown on slide 13. In the whole series of European countries, as well as the U.S. and Canada. We discussed the possibility of this drug being for both indications, that is the non-TRS add-on as well as the TRS population. They were agreeable to us looking at having one positive study in both indications and discussing the results with them to see if this would be adequate for the full approval process. In addition, the FDA asked us to do some additional work, which was associated with looking at potential risks. All the preclinical work that the FDA requested has been completed and submitted. We've completed the four-week EEG study requested by the FDA, and the remaining data that the FDA requests, basically, we expect to be able to submit once we have finished with the Study 014 results, and we are submitting that report. Now we can go on to slide 14, which is the TRS study. Before I go into that study, let me explain to you a little bit of the background of the study, because I'm sure all of you have lots of questions. At the time when we planned the study and initiated in late 2019, early 2020, we didn't have any data on TRS patients. There's always a theoretical concern that by inhibiting glutamate, you may actually worsen things. Therefore, investigators were reluctant to go into a double-blind, placebo-controlled study. What they felt was that they would rather do a study in which the principal investigator was unblinded. They would not really want to have a control group. They would rather really concentrate on the drug. This would be a randomized study. The efficacy ratings will be done by a rater who was blinded to which dose the patient was receiving. There were going to be three doses in this study: 7.5 milligram, 15 milligram, and 30 milligram BID. Based upon the fact that we were very considerate, conservative, we agreed to start the study at 7.5 milligram and 15 milligram, perform an interim analysis to demonstrate that there were no safety concerns, and then randomize patients to the 30 milligram also. So we would change the randomization to make sure at the end we would have a similar number of patients. The objective of this study, as you can determine, was really safety and tolerability first. Nobody has ever treated TRS patients on antipsychotics with a glutamate release inhibitor. So that was the primary objective. We took patients who were psychotic. They were all on an antipsychotic. Their scores on the PANSS were anywhere between 70 to 90, which means moderate to almost severe. We excluded patients who were very severe because those patients may require hospitalization, and that we did not want to do that at this stage. Of course, we did all the efficacy measurements, the PANSS, the CGI of severity, the CGI of change, the level of functioning, et cetera. Another question you may be considering is why is it that we are only reporting the 100-patient data and not the full phase study? Because we did an interim analysis. The safety monitoring board wanted to see the interim analysis before agreeing to the 30-milligram dose being included in the study. We did it and showed it was safe, so they could include the 30 milligrams. The board also felt that since we had quite a lot of patients in the study, they wanted to be reassured that the drug was doing something and not just that we were giving patients an inert drug. They requested us to do a blinded analysis of efficacy for the first 100 patients who completed the 6 weeks. That's what we did, and those are the data that were released in June and showing benefit, and we will go over that. Overall, the study enrollment has been completed with 161 patients who were randomized. There is a gap between the 100 patients going in and the 161 going in. Why is that? Because we were very unfortunate to have the pandemic hit us at the moment we started the study. While we could get the first part of the study done in enrollment terms, we really suffered a lot after that because, as you imagine, the hospitals were closed, centers were closed, patients could not travel. Enrollment really suffered. Therefore, the first 100 patients we got in relatively early, but the last 61 took some time. They have completed their enrollment, and we expect to announce those results in February, March. Let me just also point out some of the other essential questions that will come. Why are you not breaking it down by dose? Because this remains a study which is still blinded for the dose. We do not know, the investigators do not know what dose each patient was on. The first 100 patient data is largely comprised of 7.5 milligram and 15-milligram BID patients. There are only about a handful of 30-milligram patients because they were the ones who were admitted into the study late. Another question which is to be expected is really, why is it that you are not showing the exact results for week 30, although you did show that for week six? Well, we're chagrined by the fact that by showing you the week six, when we tried to put that into posters, et cetera, afterwards, or publications, we were told by all the journals that since the data are in the public domain, we cannot publish this. In this case, what we have done is we've given you information which is providing you some idea of the results, but not the exact numbers, and those will be released at upcoming congresses and publications. I think I've gone through up to slide 15, most of the things that we have required. Let me just repeat once again. We have 100 patients who were included in this analysis. Three of those patients discontinued. One patient withdrew consent, and this I'm talking about week six now. One patient basically discontinued because had severe high fever, vomiting, nausea. We had 97 patients who were eligible for efficacy analysis and completed the 6 weeks. Out of those 97 patients, 90 entered the extension. Seven did not because of withdrawal of consent, adverse events, et cetera. The analysis population here is 97 patients for whom all results are based. If you go to slide 16, you can see the results for the PANSS. We start off by a score of around 80. That may not sound very high to you, but please note that these are not patients who are on monotherapy, in other words, on placebo. These are patients on an antipsychotic. If we were to take away their antipsychotic, their scores probably would jump by another 10 points or so. When I saw the six-week data up to day 43, they were interesting, not overwhelming. It was a gradual improvement, but one could not say that these were outside the reach of placebo change over time. There's some characteristics of these data which suggest otherwise. Placebo change tends to be somewhat rapid. This is a very gradual improvement that you're seeing. My assumption was that if this is a real effect, when we look at the six-month data, I would expect to see many of these patients going back to their original baseline or maybe worsening slightly, improving slightly, but not doing much more than that. When we look at the week 30 data, I have to say I'm astounded because the effect continued to improve. I can grant you that you could have a 10-point change on the placebo, from placebo in TRS patients in six weeks. It's difficult for me to believe that these patients placebo will continue to improve over six months of treatment, over six months of time. If that was the case, I think we should market placebo for all TRS patients. As you can see on the right-hand side, we've shown you just the change from baseline and what the exact values were, but not the value for week 30, which is still will be released at a later time point. The next question comes, is this improvement of any value? Is this meaningful for the patient? Once again, on slide 17, what you're seeing is a PANSS total score responder rate. The responder rate here is not just anybody who has improved by one point. This is known as clinically important improvement in TRS patients and has been defined on the basis of clozapine studies done by the VA Hospital. A 20% reduction is considered clinically important improvement. What you can see, there's a slow degree of improvement in the number of patients who are responders. Over time, they're increasing up to day 43, which is 16%. When we look at week 30, again, it's a very dramatic finding that the number of patients who are responders, clinically important responders, doubles at week 30. Again, going back to my previous argument, 16% responder rate to placebo. You could say that it's possible. You could not say that it's impossible. Why would placebo continue to produce such a significant improvement at week 30? The longer the patients are continuing on drug, they're continuing to benefit, and the number who have a clinically important improvement keeps on going. I should just mention that a change in the PANSS and the mean change compared to baseline is statistically significant using the paired t-test. Moving on to slide 18, which gives you the change in the Clinical Global Impression of Severity and the Clinical Global Impression of Change over time. First of all, looking at the Clinical Global Impression of Severity, this is a judgment call by the treating psychiatrist as to how sick is the patient. Not at all sick, very, very sick. Not at all sick is rated as 1, very severely ill is 7. The baseline mean rating tells us that patients were between moderate and moderately severe when they came into the study. Once again, paralleling the change, what we saw in the PANSS, you see a gradual improvement up to day 43. Again, at six months, these patients show a further improvement in the level of severity. The CGI of Change is a difficult rating to understand because there is no baseline. Again, there, 1 means excellent improvement, 7 means more severe worsening. Up to day 43, you can see the patients are improving, and 3 means mild improvement. Again, in keeping with what we saw on the PANSS and on the CGIS, at week 30, there is a further improvement. In other words, the physician is feeling that these patients are improving even more than they had improved before. Next slide, which is looking at the CGIS responder rate, which is now the Clinical Global Impression of Severity. How many patients improved on the CGIS? Again, you see a small gradual increase over time to day 43, where it looks like about more than half the patients have improved in severity of illness. At week 30, again, there is a further improvement on that. Overall, what we feel here is that also looking at the CGIC responder rate, if you go to slide 22. The first 100 patients, if you look at all the results here. The CGIC, we looked at responder rate by the characterization of how many patients improved by much improved or very much improved, not just minimal improvement. Once again, we find that there is a very significant improvement there. This is the third last row on the slide, you can see at week 30, there is a further improvement on this. Whether we look at the PANSS, whether we look at the CGIS, whether we look at the CGIC, there is a continuous improvement over time. It's almost like as if the drug is producing a healing, and the slow healing are continuing. On the safety side, there's nothing to report. The completer rate is very high. At 30 weeks, we have 85 patients of the original 100 who completed. The dropouts due to side effects are only 2. There's no significant side effects. There is no reason for any patient to be withdrawn because of abnormal laboratory values or seizures or anything of this type. In conclusion, when we get to this, on the next slide. The addition of evenamide was very well tolerated. All the efficacy measures show a gradual improvement over time, which is continuous, raising the possibility that higher doses even might show a better improvement than what we have. The CGIC ratings, which is done by a psychiatrist based upon a holistic interview with the patient and not driven by a scale, indicates the clinically significant responders increase over time. The two measures we have not talked about today are level of functioning and Medication Satisfaction Questionnaire. Surprisingly, the benefit that we saw in the PANSS and the CGIC and the CGIS is reflected also in the level of functioning, where patients showed a greater improvement, a significant improvement in the level of functioning. The Medication Satisfaction Questionnaire showed us that the patients all like the drug, and they are in favor of continuing on the medication. Moving on to slide 23. Phase II-B and III, we will have the Study 8A, which is the non-TRS study just started. It is a four-week randomized study, double-blind, placebo-controlled, evaluating the effects of 30 mg BID of evenamide versus placebo in patients who are on a second-generation antipsychotic and who are at a controlled dose. These patients have to be psychotic. They have to have measurable levels of positive symptom pathology. We expect that we will have basically 260 patients enrolled for the final analysis, and the results will be expected in 2023. On the right-hand side, you see we will be starting the new TRS study, which will be started this year. This will probably be a 10-week randomized, placebo-controlled study. The doses we will be discussing with the health authorities, but will probably be 15 and 30 mg BID. Will all be outpatients with treatment-resistant schizophrenia, meeting the TRRIP criteria. Will all be on therapy with an antipsychotic and receiving treatment as usual. We will be including clozapine. We expect to have at least 450 patients included in the trial, which will be a global trial, and we expect that it will take about 18 months from the beginning to the end to complete in the field. With that, I turn it over to Stefan. Thank you, Ravi. I think now is the time for the Q&A. I will hand over to Sandra to explain exactly the procedure of how to raise questions. We will now begin the question and answer session. Anyone who wishes to ask a question may press star and 1 on the touch-tone telephone. You will hear a tone to confirm that you have entered the queue. If you wish to remove yourself from the question queue, you may press star and 2. Participants are requested to use only hands if they are asking a question. Anyone with a question may press star and 1 at this time. Once again, to ask a question, please press star followed by 1. The first question comes Leonildo Delgado from Baader Helvea. Please go ahead. Hi. Good afternoon. This is Leonildo. Happy New Year, and thanks for taking our questions. Any ideas on how the design of the pivotal Study 003 might look like? I'm thinking if placebo will be used, what will be the expected efficacy and safety levels? Sure. The study, as I just probably mentioned very briefly, will be minimally a 10-week placebo-controlled study in which we will have patients with chronic schizophrenia who have been demonstrated to have failed at least two antipsychotics, of which one must be a second-generation antipsychotic, who are compliant with their medication, who will be having PANSS score of above 70 while on an antipsychotic, who will be having a CGI of severity of at least moderate, and who will have a responsible caregiver. These patients will be randomized to 15 or 30 milligrams or placebo on top of whatever medication they're taking. We have had extensive discussions in the past about the outcome measure, what it should be. We would have favored more like a composite measure comprised of symptom scores, CGI of severity, CGI of change, et cetera. Whether it be the FDA, EMA, Canada, all governments have said no, they want it to be based upon the PANSS total score. In general, what we estimate is that the minimum clinically significant difference in TRS patients will be six points compared to placebo. That may not sound like much, but in TRS patients, first of all, you do not get a very big change. Second, these are TRS patients on an antipsychotic. Therefore, the change that you may induce is already attenuated by the fact that there is an antipsychotic already on board. That's what is considered to be clinically significant. Thank you. Can I ask another question very quickly? Sure. Given that evenamide will be used as add-on, are regulators likely to prefer a lower dose on a potential hypothetical approval scenario? Yeah, sure. I wanted to see. Mm-hmm. Let me answer that question. First of all, for evenamide, the dose will be whatever it is. I think 15 and 30 milligram BID. Those are the two doses we're proposing. I think what you're really asking is, if the drug is working, is there a need to keep the risperidone dose at six milligram or eight milligram, or olanzapine dose at 20 milligram? That is something which I think will be left to the hands of the treating physician. That once they begin to see the efficacy of the combination, they will probably reduce the dose of the previous antipsychotic, and therefore reduce the amount of side effects that are associated with the previous medication. Thank you. That answers my questions. The next question comes from Bob Pooler from ValuationLAB. Please go ahead. Thank you. First of all, Happy New Year, Stefan and Ravi. Pardon me. Also congratulations on the exciting interim results of evenamide in TRS patients. A few questions from my side. First, on the studies of 014 and 015, what you presented here. Do you have an idea if the improvement seen is due to the duration of treatment, so six weeks versus six months? Or is it due to more patients receiving 30 milligram twice daily dose? Sure. Bob, first of all, the 100 patient data that we are presenting, they are the same dosage as it was in the six weeks. There's no new patient in the six months versus the six week. It cannot be an effect of dose. It is an effect of duration. I don't want to get into the theory of how treatment resistance works. There's long been a belief that in clozapine, the six-week study probably underestimated the benefit of clozapine. There've been some investigators who have always said, "Clozapine, if you continue longer, produces a greater benefit." I don't want to say this drug is clozapine. I think we are not there yet. To me, it seems difficult to understand why a patient who has responded to a certain extent at six weeks will continue to respond at six months if it is not due to drug. That's the best way I have of answering your question. Okay. Just going forward, if you look at Study 015, the one-year extension trial, what will your expectations be? You have and a longer treatment duration, and you have probably also the higher dosing, more patients on a higher dose. No, the extension trial has the same dosages as the main trial. If the first 100 patients had about 92 patients on 15 and 7.5 milligram, only eight patients on the 30 milligram. In the remaining 61 patients, we change the randomization, there will be more patients on 30 milligram. Theoretically, yes, you're right. Those 30-milligram patients, when we do a dose analysis, should produce a better benefit. As you know, with CNS drugs, there is no linear progression of efficacy with dose. Yeah. As you saw with the lumateperone, I mean, the lower dose turned out to be effective and not the higher dose. My expectation is this is a good enough result for me at the moment. If we could just continue to show this, that would be great. 30 milligrams having a larger effect is biologically very plausible. Okay. Then for both of you gentlemen, what is the most exciting result in this data set? What do you believe is most exciting for you? For me? Stefan. Also for Ravi Anand. I think for me, what is most exciting is the CGI of severity result. The fact that the PANSS is a scale. You're scoring every item from one to seven, and you feel sometimes constrained to give a rating because the scale demands it. The CGI of severity and the CGI of change are done by a psychiatrist based upon holistic interviews with the patient and observing the patient. What it's telling me is the psychiatrist is able to see something in the patient without the help of any scale, which tells them that the patient is doing better. That to me was one part of the story, which is very exciting to see that one. The second part I think which is exciting to see is the fact that the continued improvement at six months really makes me, pardon the expression, the believer more than the six weeks data. How could you have a placebo response improve over time? That's never been the case till now. Secondly, the fact that there is increasing improvement in patients, it suggests to me that we probably need to consider longer-term treatment in these patients. If I may add, Bob, what I find the most exciting from my point of view, this is the first study in TRS patients with evenamide. Remember our theme, our theory was that it is fully due to glutamate imbalances that we see the treatment-resistant patients. I think what we are seeing today is a potential proof that this thinking was absolutely right and it works out in patients, and it is not due to a short-term placebo benefit. We are very much looking forward after six weeks and six months. The next thing is that we will look at one-year results. We are very much appreciating these results, but we want to see the next thing now. Well, again, if you look at Study 014, it's the final FDA safety trial. I think that's required to start the pivotal phase III Study 3 trial. The primary endpoint is actually safety and tolerability after 16 weeks. Yeah, are you surprised to see these exciting improvements after six weeks and six months treatment in particular on, let's say, the secondary endpoint is efficacy? I think basically the FDA's concerns originally came from safety concerns, right, if you remember correctly. We have by now supplied enough animal data to be able to address that issue. We have supplied data from EEG studies. I didn't go into the detail of it because it's just useless. We have done EEGs in over 250 patients or so. We have no abnormal EEGs. We have done seizure checklists of a few thousands. There's not a single symptom there. We have done plasma level monitoring in patients who are 2D6 poor metabolizers. There's no significant increase. From the safety point of view, we have considered it all. We will have data from the Study 008A, which will also feed into the submission to the FDA, which we expect to do sometimes in the end of the first quarter or the early second quarter of this year, together with data from 161 patients with TRS. From the meeting the FDA point of view, I think safety-wise, it's definitely very convincing. This is, of course, an open-label study with a randomization and with blinded raters. This was a design that I had used also for the clozapine approval for suicidality. The FDA is not new to these designs. Again, I think the strength of the data lies in the fact that the long-term data is showing benefit. Mm-hmm. Two questions, if I may still. I saw Study 003 in TRS. I saw the treatment duration has been increased to 10 weeks- Yeah from previously eight weeks. Is that the reason why you're saying also it might take longer to see the treatment effect? Yeah adding two weeks would be better. Yeah, Bob. You touched on a topic I didn't want to get into, but okay. Originally, I had proposed a six-week study- Okay which is the standard for all schizophrenia studies. The FDA basically said no, eight weeks. We have been getting input from various regulators on different durations. Looking at the data from this study, it tells me the six-week would be a mistake. At the same time, I don't think we can do a pivotal study for six months. We temporized by saying 10 weeks, looking at some of the data that we have, looks adequate. However, after the 10-week period, patients will continue on their randomized medication. We will not be breaking the blind and putting them on open-label treatment. They will continue blinded. The primary endpoint will still be 10 weeks, but we will have the patient continuing long-term up to one year. Okay. My final question. With this exciting data, do you see more interest now in partnering coming forward and just on the sort of timing of partnering on this data, would you yeah, be interested in partnering, or you would still wait until you have the Study 008A results data? I think, Bob, it has become very obvious that this evenamide should now get into the second pivotal study without any further delay. That is why a second pivotal study should start this year, given that we need six, eight months preparation time to get it started. We don't want to waste time. That is why we are intensifying our partnering discussions. Remember, we have different models. It might be a local, regional, or global transaction. We certainly need to keep some control of the development process. That all still applies. Now, given these outstanding results that we are looking at, we do not want to lose time. Yes, we might prepare and partner ahead of the 8A results. Okay. Very clear. Congratulations again, fingers crossed for the future results. Thank you. Once again, to ask a question, please press star and one. The next question comes from Samir Devani from Rx Securities. Please go ahead. Happy New Year, everyone. Congrats on the data. Very encouraging. I guess I've got a few questions. First one, Ravi, why do you think it's taking so long for the treatment effect, and is there any precedent in this field for an effect to take so long? I guess that's the first question. Okay. Let me answer it one by one because it gets complicated. Yeah. The problem is that there's not too many long-term studies in treatment-resistant patients. We have no real massive database to talk about what happens in these patients. The only study which we know really was positive was clozapine Study 30, which was only six weeks. There are other studies. There is a study by Rosenheck, which is this U.S. Veterans Administration hospital study comparing clozapine to haloperidol in treatment-resistant patients, and that shows some similarities and some differences from this study. In that study, compared to six weeks, the six months data for clozapine change looks like it improved. Haldol did not improve. On the other hand, the responder rate for clozapine at six weeks does not change at six months. That's the best I could tell you. There are a couple of other studies which are based upon 20 patients, I don't want to theorize based upon that. To me, it looks like this, in treatment-resistant patients, because they've had so many years of damage by the antipsychotics given, there is a slow process of repair. That's the only thing I could tell you, and that's based upon some of the data. Again, I keep referring back to clozapine, where it shows clozapine, when it's given to patients with severe tardive dyskinesia, does not produce an immediate improvement. By the end of six months, there's a massive improvement. It looks like the glutamate system is able to shock the other systems to start working, but it's not like pouring a bucket of water on fire. It takes much longer. That's one of the reasons why I think, as I just mentioned in the previous answer, we extended the study to 10 weeks. Okay. That's helpful. I guess the second question then is just trying to think what potentially could prevent you kicking off this pivotal 003 trial. Is there anything in 014 when you release the data in March that could throw us a spanner in the works? For example, if you don't see a dose response when you report the full data set, will that require you to do some further work before you kick off 003? No. I would actually argue in just the opposite. The fact that even lower doses were showing better efficacy, well, the same efficacy as 30 milligrams, that means the risk-benefit ratio improves. At a lower dose, you're getting a better effect without having the potential baggage of adverse events. That would not prevent us. Assuming that you'd need to explore some lower doses in the current, right? Well, we do have 7.5 milligrams. The question would be basically that do you absolutely need to define a minimal effective dose? I think that's basically probably what the question you're getting to. With antipsychotics, the FDA has not really stressed that point. Neither has EMA, although we do technically say that we should try to do that one. What we would do probably is in one of the additional studies which we would have to do, we would do a lower dose, such as 7.5 alone, and see what happens with that. Okay, that's great. Just a couple of questions on the non-TRS- arena. In terms of 008A, how many patients have you now enrolled in that study? Approximately 100. Okay. If we're looking at the key competitor seems to be Karuna's KarXT in the sort of non-TRS space, how would you compare and contrast the ARISE study to what you're planning to do? I think it's very different in a way. First of all, the mechanisms of the two drugs are totally different, right? That's a given. In a way, I actually welcome the fact that Karuna, if it gets approved, that presents to us another drug we could add on to once patients stop responding to Karuna, but that's a long-term hope. In the meantime, I think the entry criteria are more or less similar. We have put in some safeguards in the [18 study], which I'm not sure everybody else has done. You probably may remember that we are doing very significant monitoring of plasma levels of the previous antipsychotic to make sure that nobody gets in who is not taking their medication and claims to be an inadequate responder. That's usually not done, and I can tell you it's not done because it's pretty painful to do that, and you find out all kinds of things. Second thing is, our insistence is on having only one antipsychotic. You can believe the patients when they say they're taking one antipsychotic, and when you test their plasma levels, you find there may be one, there may be two, there may be antipsychotics which the patient is not even claiming to be taking. From methodological point of view, we put in a lot more into this study that we've done. Overall, otherwise, there's no real difference. We're still measuring the same scale and everything else. Yeah. Okay. That's very helpful. Thanks very much. Congratulations on the data. Thank you. Ladies and gentlemen, that was the last question. I would now like to turn the conference back over to Mr. Weber for any closing remarks. Yeah. Thank you very much all for staying with us, staying tuned for this extended call. I think it was very important that we went through the details so we all have the same understanding of what we have just presented to you. I can only close this call in saying stay tuned for the future as well. We will show to you soon the complete results of Study 014, including all 161 patients. We will then have the one-year results, as mentioned before, on the first 100 patients. We will then have the full Study 015, so 161 patients, one-year results, next year. On our way, we will start the second pivotal study, and we will get the results from the first pivotal study in non-TRS patients. A lot to come, a lot of news flow. Stay tuned. Thank you very much for attending, talk to you soon. Thank you. Ladies and gentlemen, the conference is now over. Thank you for choosing Chorus Call, thank you for participating in the conference. You may now disconnect your lines. Goodbye