Ladies and gentlemen, welcome to the Newron Conference Call, reporting exceptional one-year results of Study 014, 015 with evenamide in treatment-resistant schizophrenia. I am Alice, the conference call operator. 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. Thank you, Alice. Good evening, I should say, to our listeners in the East. Good afternoon to the European listeners. Good morning to those in the United States. Happy New Year to everybody. For sure, if it should continue the dynamics we have seen lately in antipsychotics markets, it should be a good year for Newron. I'm here today with Ravi Anand, the Chief Medical Officer, who is today dialing in from New York, who will take on the presentation of the exciting one-year results this call is about. This refers to Study 014 and 015, in which evenamide was tested as an add-on therapy to any second-generation antipsychotic in patients who are treatment-resistant. I trust that you have downloaded the slide deck for this call from the website or via the link in the press release. As Alice has just said, we are looking forward to the Q&A session later on. Newron is all about drugs development in the CNS space. Takes us to slide one, all innovative. We are listed on the Swiss Stock Exchange since 2006, with our shares also being traded at the Frankfurt, et cetera, and the Düsseldorf Stock Exchange. Please read carefully the disclaimer on page two. After 20 years of existence, Newron should have a drug on the market using or applying the usual timelines for taking a drug on and taking it through all the development stages to the market. Here we are, our first drug, Xadago, an add-on treatment for Parkinson's disease was approved in the year 2015 in the European Union, in the year 2017 in the United States, has been marketed for a number of years by our global partners by now. If we can say one thing about this Xadago, which comes from the same source as evenamide, the drug we are focusing the call today on, it is a safe drug and it works in CNS diseases. For investors, you might say, well, it's on the market for 8 years now in Europe and for six years in the United States. It's a nice royalty stream. There is no substantial upside to come from that compound. The real upside for investors is with evenamide. It's again, a voltage-gated sodium channel blocker, just like Xadago is, it offers a new concept in treating schizophrenia in two indications, one, for inadequate responders, and number two, for those patients who are treatment-resistant in schizophrenia. We are looking for additional efforts to complete the pipeline or to complement the pipeline. The management that is running Newron has taken a number of compounds to the market besides evenamide, which we took on in early preclinical and took to the market. Ravi Anand, our Chief Medical Officer, has been in comparable positions with Novartis, Roche, and Organon CNS branches. We have massive news flow reported. You have seen just before the end of the last year, we did announce the completion of the enrollment of our first pivotal study with evenamide in schizophrenia. That is the indication where patients are not yet treatment-resistant. The results from that pivotal study are expected by the end of Q1 of this year. Today, we are talking about the phase II study, one-year results in the second indication, those patients who are treatment-resistant. More news flow to come in the next three, six, and nine months. That is a partnering, and the start of the pivotal study in treatment-resistant schizophrenia. We are funded beyond the inflection points. We do have a cash balance as the last June of EUR 17 million. We have an ongoing income of royalty and R&D tax credit from Italy that is about EUR 8 million per year, so our cash reach is into Q3 of this year. Let's switch to evenamide, which is offering the potential to change the treatment paradigm in schizophrenia. It's a large market. We are talking about 1% of the global population. Just to highlight to you how big and how important this market is, I spoke about the late dynamics in the antipsychotics market. You have probably seen the news from November, early December, when a company called Cerevel was acquired by AbbVie for $8.7 billion. Cerevel has most advanced compound being a schizophrenia treatment, in a phase I-B status with two phase II studies ongoing. Just to add on, just a few days ago, you might have seen the news that one of our peers, Karuna, who are a, I would say one-product company around a drug in schizophrenia this point in time, have been acquired for $14 billion. I will admit that Karuna has filed the dossier for approval for marketing with the FDA, so they're slightly ahead of us. That shows you the kind of interest and the excitement right now for innovative treatment for schizophrenia in the market. We should not forget the last approved drug, which happens to be Intra-Cellular Therapies's CAPLYTA, which is on the market now for three years, that has been launched by the company itself, Intra-Cellular Therapies, in the United States. And after three years, the annualized sales of that compound in the U.S. alone are $500 million, way ahead of the five years that it usually needs to take a drug to peak in CNS indications. They are doing it themselves. They are at $500 million annualized sales after three years. This confirms the statement that any slightly innovative drug in schizophrenia will be a blockbuster. Now, what does evenamide offer? It offers a unique mechanism of actioning and positioning. We are the only drug under development, no competition left, no right, no one, 2 years behind, offering a glutamatergic mechanism. We are the potentially first drug to be approved as an add-on therapy in schizophrenia. The simple reason for that is that so far all the drugs on the market do work by the same mechanism, an add-on would simply be kind of an increase of dose and increase of side effects. There is no approved add-on therapy right now for schizophrenia. evenamide being approved as an add-on treatment would change non-responder into responder. There would be no need to change the current therapy when more than 70% of patients come back to their doctor and say symptoms are coming back. There's no need to take them off their current medication to wash them out, to titrate them up slowly on the new medication. No risk of relapses, no hospitalizations, no risk of increased suicidality due to that switch of medications. Just stay on your current medication, add evenamide, get the additional benefit. No incremental side effects of relevance seen so far. Ease of use for patients and physicians. No risk, less cost. The first indication that we are currently developing evenamide for is add-on therapy in those patients who are no longer seeing the full benefit from their current medication, chronically schizophrenic, but not yet treatment resistant. Besides that is the second indication, that is the indication that we are indeed focusing the further regulatory path on. That is that evenamide beyond [inaudible] clozapine, which has been on the market since the late 1980s but is massively underused. It would be the one and only therapy beyond clozapine for those patients who are treatment-resistant schizophrenics. 30% of the total schizophrenic population means 0.3% of the global population are diagnosed as TRS. The upside is up to 50% doctors saying, "I could diagnose half of my patients easily as treatment resistant." I just don't do it because there's nothing I can add to them as a therapy. TRS is a huge market opportunity. Niche indication of about EUR 150 million or EUR 200 million. Those patients who are treatment resistant only to clozapine, that we might want to keep to ourselves in case we would go for licensing. There would be a nice niche opportunity for our own commercialization should we license the global rights to evenamide. What do we have to offer to you? We do already have positive results from phase II in non-TRS patients. As I mentioned before, the first pivotal study in non-TRS is ongoing. The enrollment has been completed end of December, the results from that first pivotal study with evenamide will become available by end of this year's first quarter. Changing to treatment-resistant schizophrenia, we have for you the pilot study in 161 TRS patients after 12 months, that's exactly the result that we will focus on today. With positive results from a pivotal study in TRS, one study would be sufficient to get the drug approved for marketing. Prior to the formal process of marketing, we might even get an early access in some of the territories. It might be reimbursed, in others it might be not, we would only collect the safety data and get access to the patients. Commercially, we are protected. Our exclusivity from the composition of matter patent goes on till 2033. In the European Union, we have additional exclusivity beyond, which is the 10 years data protection exclusivity. Assuming that the drug would hit the market in 2026, that would give us exclusivity until 2036. That all said, I hand over to Ravi. We are on slide five, and we are talking about the medical need for the patients suffering from schizophrenia. Over to you, Ravi. Thank you, Stefan. Good morning to folks in the U.S., good afternoon to those in Europe. Stefan has talked about broadly about schizophrenia, I think the dimensions of the population that could benefit from a new treatment are immense. As most of you already know, we're talking about over 20 million patients worldwide. We're talking about almost 30 to 60 antipsychotics available in different countries. What is unique about all of these is the fact that none of them has been shown to provide substantial relief across the spectrum of schizophrenia patients and for extended periods of time. Most of the paid drugs approved are really going to be targeting the acute phase symptoms and reducing their severity for the patient for a period of time. Again, patients generally relapse. 10%-20% of patients will relapse over a period of one to two years. What is unique about schizophrenia is it's the same disease around the world. It's got the same 1% prevalence. The age of onset in males tends to be around 18, 19 years of age. Females is about five years later. The outcomes are the same. 30% of patients usually respond to monotherapy. 30% of patients show a response which is less than adequate, and another 30% is what we call as treatment-resistant. In addition to not being able to control the progression to treatment resistance, the current antipsychotics have not shown any efficacy in treatment of negative symptoms, reducing the burden of cognitive dysfunction or maintaining patients in the community. If we move now to the next slide, which is number six, I'm just really briefly going to go over the mechanism of action of evenamide just to show you how different it is from anything else. We have looked at over 130 different CNS targets, including receptors, enzymes, transmitters. This drug does not interact with any one of those. The only thing that it does, it inhibits sodium channels, voltage-gated sodium channels, in a very unique way. If you look at the graph on the left-hand side, you see that in the resting state of the cortical neurons, you need 25 micromolar of this drug, which is like buckets of drug, to produce an effect. In the inactivated state of the channel, which is where it really must get active, in states like epilepsy, acute burst firing, you only need 0.4 micromolar. That's telling us the drug becomes active when it's needed to become active, not otherwise. The major advantage would be that it would not have side effects in patients who are not needing the level of effect that it produces. The level of effect that it produces can be seen in the middle graph, where you see the two kinds of neuron, the high frequency firing neurons and the low frequency. The low frequency firing neurons is what all of us need for our normal functioning, for neurological function, for coordination of activities, for movement, and one micromolar barely has an effect. If you look in the left-hand side, the high frequency firing neurons, epileptic states, et cetera, one micromolar almost completely inhibits this fast-firing neurons. How does it do this? It's a very simple action. All that this drug does, by the virtue of its effect on sodium channel, is control the excessive release of glutamate. In the resting state, it has no effect on glutamate. The base of glutamate is unaffected, this is the mark showing you from in vivo microdialysis. The injection of veratridine, which releases glutamate, which is shown in the black. You can see glutamate is released, peaking. The blue and the red are different concentrations of evenamide, they attenuate that release. This is the sole function of this drug in the brain, that's why it is so unique a compound to play with. If you go to the next slide now, which is slide seven. This function offers us a lot of opportunities. First of all, this is a drug which could be added on to any drug. Any drug could be added on to it. There is no other drug that's a glutamate release inhibitor, therefore, there's no competition for it at all. If the studies come out positive, as they increasingly look like, it will be the first add-on antipsychotic, acting through a different mechanism, to be approved for patients who are partial responders. As I mentioned before, at least 30% of the patients are partial responders. Generally speaking, Currently, the worst kind of patients that one can find in the clinic are those who are clozapine non-responders. These are the patients for whom there is no hope, they take up a lot of our resources. The data that we have collected to this date show that the addition of this drug to clozapine non-responders may be beneficial for those patients, that will be a unique indication for this drug. Moving to the next slide, number 8. To very quickly run through why this is unique, first of all, the structure does not belong to any known class of drugs that are used as antipsychotics. The pharmacology, as I mentioned to you, is completely unique. What we have seen in humans to this date is a very benign side effect profile, I'll go through this in later detail, just to say that the usual side effects of antipsychotics are not noted at all. There is no competitor that has been identified to this date. We have data now, which we'll be talking about in a few minutes, from 161 TRS patients. Generally speaking, you tend to see about 10% of patients having a relapse in about a period of one year. That is for garden-variety schizophrenia. For TRS patients, the number will be much, much higher. For some reason, we cannot explain, we obviously hope it's because of the efficacy of the drug. Out of the 161 patients who were enrolled in this trial, the 156 who got treated, there's not been any psychotic relapse. If that number is confirmed in subsequent studies, that would be a major benefit for positive health technology assessment. There is no EPS with this drug. There is no weight gain with this drug. There's no sexual dysfunction. There are no endocrine abnormalities. There's no cardiac dysfunction that we have noted to this date. We have done studies, specialized studies, that have demonstrated there's no QTc prolongation. There are no cardiac abnormalities. There's no pattern of any abnormal laboratory results. You do not need to monitor labs again and again. There are no other side effects of the type we did mention. ICH requires 100 patients treated for one year. We already have crossed that number. We have more than 120 patients who've been treated for a year. We have at least 500 patients who have been unique subjects who have been treated, and 400 patients with schizophrenia. All tox studies that are required for registration have been completed except carcinogenicity, which after long discussions, we have now come to an agreement with health authorities that we would not need to do a two to three-year study. We would only do one study in one species. Normally, you have to do both species, and that would be six months in genetically modified mice. That will significantly shorten the timelines to submission. For Europe, we also have to do the ERA studies, that will be negotiated at the time of discussion with the CHMP. Another major advantage is that we have got tentative agreement from authorities in Europe, including CHMP, FDA, and in Canada, that were this, the TRS potentially pivotal study, which will be the next study we will be performing, be positive, that may be adequate for getting approval for this drug under an expedited approval mechanism. That would be a major benefit, that is why we are focusing the strategy on TRS. Next slide, please, which is slide nine. Where are we now at the moment? For TRS, we have one study which is completed, the one-year data that we are presenting today. This was, let me say it right now, so there's no confusion, this is not a pivotal study. This is not supposed to be a definitive study. This was a pilot study looking at the tolerability and efficacy of three doses in TRS patients as an add-on. We designed the study in two parts, six weeks, the first part, then an extension up to one year. Both have been completed. In the non-TRS population, we already completed a phase II study a few years ago, and the second potentially pivotal study has just completed enrollment. This is a study which we will have 290 patients who've been randomized to either a placebo add-on or evenamide add-on of 30 milligrams. The efficacy data that we have to this date indicate that we will definitely show a benefit of treatment compared to baseline on the key efficacy measures in schizophrenia, which are the Positive and Negative Syndrome Scale. More importantly also, on the severity of the disease as judged by a clinical global rating performed by the psychiatrist, and also their functioning appears to improve, not just for six weeks, not just for six months, but throughout the one year. Why are we so excited about study results coming from an open-label study? Treatment in schizophrenia patients and the ones we took here were the ones who were already on an antipsychotic, and they were not doing well. We managed to get a clinically important improvement on the PANSS scale. 20% improvement from baseline in treatment-resistant schizophrenia patients is considered clinically important. We got also one-quarter of the patients improving on the Clinical Global Impression of Severity. This is 2 category improvement from baseline, not just minimal improvement, but 2 category improvement. We also have one-third of the patients being judged as much improved by the clinician. This is not just at six weeks, but we're talking about numbers going up to one year. What is unique about this study? I think all of us may have skepticism about an open-label study, non-placebo controlled. The important thing is that placebo response in treatment-resistant schizophrenia has never been seen to be sustained and over time, that as we see in this. We clearly see the benefit, which is increasing over time. Why is that so important? It tells us that patients who responded initially continue to respond. They did not drop back to baseline. More importantly also, many patients who did not respond at the beginning became responders at six months, became responders at one year. This goes against the teaching where we say in schizophrenia in general, if a patient doesn't improve in six weeks, he's unlikely to improve any further. Here what we're saying is keep faith and keep on treating patients, and if they stay on drug, they will improve. Very surprising finding was these patients who were treatment-resistant, meeting international criteria, improved to a certain extent that about 50% of the patients would no longer meet the criteria for treatment-resistant schizophrenia. This, as far as we know, is a first-time result. Last but not least, the term remission, you hardly ever hear about trials in schizophrenia producing remission of patients. These are fairly elaborate criteria. What we was really surprised to see is that at the end of the one-year period, one-quarter of all the patients of treatment-resistant schizophrenia, and let me tell you that there are no guidelines even for treatment-resistant schizophrenia showing remission. 25% of the patients met these criteria. Overall, this study has been amazing, and our confidence in its results has grown as the results have become much more solid as time goes on. Next slide 10. I'm going to talk briefly about the design of the study. As I mentioned before, it's a pilot study, six weeks followed by an extension. Again, we talked about the objective. This was not a pivotal study. It was just to gain sight, but the results have been so positive that with hindsight, I wish we had gone and done a placebo-controlled study. What we did is we took patients who by history had not responded to at least two different medications, antipsychotic medications. This had to be a documented history. The patients must have failed these antipsychotics in trials of adequate length, which means at least four to six weeks, and a therapeutic dosage. Since TRS patients cannot be managed just on water, they were all on another antipsychotic. Again, they were not responding, otherwise they wouldn't be treatment-resistant. They were not responding to this drug when they'd come into the study. This could be any antipsychotic, first generation or second generation, except clozapine, because it was felt to be too difficult or risky at that stage to be asking patients to come in every week for a clozapine blood test, as this study was run almost concomitant with the pandemic, and the issue of patients visiting centers was very difficult. The efficacy measures are the same as in any other trial, and all the readers were basically certified. The severity of the patients we chose was 70 to 90 on the PANSS scale. Some may consider that somewhat low, but please note that these are patients who are scoring this while on an antipsychotic. If you had taken the antipsychotic away, probably the scores would have worsened by at least another 10 points. In addition to the total score, we also had a requirement that the core positive symptoms, the symptoms that really drag a patient to the attention of the psychiatrist, were scoring greater than 20. The CGI of severity of disease was at least moderate to severe level. These are scores while on an antipsychotic, without an antipsychotic, it would be even worse. Suicidal patients, of course, were excluded. We started the study in India, Italy, and Sri Lanka, but as unfortunately because of the pandemic situation, both Italy and Sri Lanka contributed very little. The next slide, which is slide 11, is a description of what happened in the study longitudinally. We randomized 161 patients to one of three doses, almost equally. This is in Study 014, which was six weeks duration. At the end of six weeks, patient who completed had the choice to continue or not to continue the extension. Out of the 161, 153 completed six weeks, which is a number which is extraordinarily high. You hardly ever see a dropout rate less than 10%, 20%, even in a six-week study. We had a very low dropout rate. As you can see from here, there are only about eight patients who discontinued. Of the patients who completed the study, 144 out of the 153 chose to continue. That can only imply that they see a benefit and that there are no side effects. When we got to the six-month stage, out of the 153, 132 completed the study. Basically, out of those, 12 discontinued in that time period. When we got to one year, we have 121 patients out of the 153 who completed the six-week period. Most common reason for withdrawal from not going into the full one year was a withdrawal of consent because patients chose not to come to the clinic any further. Dropouts due to adverse events are only two, and one patient died after about six and a half months of treatment suddenly of a cardiac cause. We have now one-year data from the 121 patients who've completed the study, and all of our analysis are based upon the standard ICH E9 requirements for analysis of studies as we go to the next slide. Let me first give you the summary of the results. Less than one-third of the patients experienced any new treatment-emergent adverse event. There are two serious adverse events that occurred during the study. One was a death, which after six months. This patient had improved quite a lot in terms of the psychosis. There are no any other adverse events, and as you probably know that in schizophrenia, sudden cardiac death is one of the commonest causes of death in this patient population. An autopsy indicated some evidence of atherosclerosis. There's a second patient who did very well in the study, was off medication for more than 20 days, and as was not followed very carefully by the relatives, went and kept on drinking a lot of liquids. As you know, in schizophrenia, there's a condition in which patients keep on drinking so much liquid, they call acute dilutional hyponatremia, which then leads to a seizure, and that occurred in the study. These are the only two serious adverse events. There are no other extrapyramidal side effects, endocrine effects, metabolic syndrome, sexual dysfunction, CNS effects, or laboratory abnormalities. No patient relapsed during the 1 year of treatment. We have an independent international safety monitoring board comprised of a chairman from Rush University in Chicago, another schizophrenia researcher from Baltimore, and a cardiologist from Chicago who regularly review all the data. Based upon the data that we have now, it is very clear this drug could be added to any antipsychotic. Any antipsychotic could be added to this drug. It seems it's ideally suited for the treatment of TRS patients. Why do I say that? If you look at the next slide, which is slide 15. This is a positive and negative symptom scale. This is the scale based upon which all health authorities judge the efficacy of a drug. You can see from baseline onwards, of all the patients who entered the extension study, there is a reduction in scores as time goes on. Now, at the end of 1 year, this is almost like 20%. Why is this so important is basically, again, the progressive reduction indicates a mechanism which is very difficult to explain. Usually, we do not see this with neurochemicals. We see an abrupt reduction and then plateaus out, a very minimal change. This looks like a sustained reduction over time. I don't know it's possible to say what would have been the results if you had done one and a half years. It may have increased even further. But at least for 1 year, we're seeing a 20% reduction in the PANSS total score. If you go to the next slide, which is the positive symptom score, but now showing you the responder analysis, 20% reduction is considered clinically important. You can see that again from week 18, where we have a 25% of the patients who are responders, it jumps to 34% and then to 41%. The proportion of patients who are meeting the 20% criteria is increasing over time. In other words, patients who had not responded at six weeks, which we are not showing you in this, that was in studies 14, who had not responded at six weeks, responded at week 18. Those who had not responded at week 18, some more joined in at six months. Those who had not responded at six months, many more joined it at one year. The number of patients who attained clinically important response also increases with time, not just the magnitude of the change. Next slide, which is slide 15. The clinical global impressions of severity of illness. Why do I stress this so much? I think for the psychiatrist, generally speaking, scale scores are meaningless. We do not go around talking about this patient is 82 or 84 or 36 or 37. What we do really talk about is how severely ill is the patient. Is he mildly ill? Is he moderately ill? Is he severely ill? We generally rate this on a seven-point scale. It's done by a psychiatrist who's very well experienced with the method of treatment. As you can see, patients came in the study of a score of 4.5 means they are between moderate to moderately severe. By the time they exited the study, they were down to a score of 3.5, which means between they're mild to moderate. It's a 1 category change you can see in the means, but the means tell us nothing. Let's look at the next slide, which will be slide 16. Now you see the real picture beginning to emerge. We're looking at patients who improved by 1 category. If you look at it in 1 category, it looks like almost 75% of the patients improved in the severity of the illness at the end of one-year period. The patients who were severe moved to moderately severe. Those who were moderately severe moved to moderate. Next slide. This is now showing you the final two scales of the study, the clinical global impression of change, which is the psychiatrist does an interview with the patient. It's not a scale anymore. Just based upon an interview where he talks about how the patient is doing, how the patient is feeling, how he looks at him and assesses how he's dressed, how he's talking. Is he oriented in time? Does he still have belief that he's hearing the voices? He judges the patient as either no change, minimally improved, much improved, very much improved, or minimally worse, much worse, very much worse. As you can see in the graphs, the pink color graphs tell us that by the end of one year, one-third of the patients were considered as much improved, not minimally improved, much improved. Again, consistent with the symptom scores, there is an increasing effect over time. Lastly, we have the level of functioning scale, which measures functioning. What we see here now, compared to baseline, again, there is an improvement in the symptoms in the items that assess functioning in these patients. Next slide. This finding, which I had mentioned to you, is very unique, at least for me, which is to see that the patients who came into the study no longer meeting the criteria for treatment resistance. How did we select patients with treatment resistance? First of all, they had to have schizophrenia history. They needed to be having disease for at least 5 to 10 years. They had to be moderately ill, at least. A PANSS score had to be greater than 70. A score of four or more on the core items of psychosis. What are the core items of psychosis? Conceptual disorganization, hallucinations, suspiciousness, unusual thought content. The score of these four must be moderate for at least two of these. A total score of greater than 20 on all the positive symptoms, which are listed down below. On the next slide, which is slide 19, I show you the results for each of these items. In the interest of time, just let's go to the last column, which is showing you the one-year results. We have taken the liberty of showing you both the LOCF, which is the last observation carried forward, and the observed case analysis. The difference being observed case means only those patients who were present at that time, and the LOCF means patients whose score has been carried forward, even if they have dropped out before. Remember, the dropout rate in this study is very low. As you can see, 84% of the patients were still there at one year. Well, 84 patients rather, no longer meet the criteria of score greater than 70. Likewise, the core item score, 66% of the patients have scored on less than 20. The severity of the disease is judged to be less than moderate in 63%, and score of four or more in one core symptom is now not met in 72% of the patients. Overall, if we combine all these criteria, 55% of the patients are no longer meeting the criteria for treatment resistance. This would be a wonderful thing. It means a patient who was not responding to any medication, the addition of an NMI has now made this patient benefit from treatments. Last is a term which you never really hear about in a trial, which is remission. Remission is not response, it's not benefit. It is much, much more than that. First of all, means you have the symptoms are down to a level that an individual's behavior is not affected at all and would never be diagnosed with schizophrenia. Symptom improvements must not be for a week or two weeks or a month, at least six months. Why is remission so important? Long-term studies have shown us that those who achieve remission status, they are much better long term. It also sets a minimum standard for the minimum severity of symptoms that these patients must be having the symptoms absent to remain at this level. If you go to the next slide 21. There have been very few studies done trying to understand even what is remission. There's one study from 1993 from Jeffrey Lieberman et al. They used the scale known as the Schedule for Affective Disorders and Schizophrenia, and they defined certain items of that scale and made it a requirement that no item should be more than three. That CGI of severity should be less than three. The CGI of change means must be much improved, but he only required eight weeks. In the latest version that has been published, which is in 2005, Nancy Andreasen et al. redefined it using the PANSS scale. They noted down certain items of the PANSS scale, which they felt were very critical for remission. Virtually all of these items, the scores have to be below three. They basically required that this level of change should be maintained for six months, at least. We looked at both of these criteria. For the first one, we had the impaired understandability, which is in the Lieberman criteria, is no longer present in any scale, so we replaced that with a suitable transferable term, which is avolition, which is conceptual disorganization. Bizarre behavior also, we replaced it with mannerisms and posturing from the PANSS. Let's look at the results on the next slide. To my immense surprise, 25% of the patients, doesn't matter which criterion you use, meet the criteria for remission. Surprisingly, the Andreasen criteria, which requires six months of reservation of symptoms at a low level, were also met. This is a fantastic result. We hope that we can build upon it in the next few studies. These data were very critical for us to decide to move into the next trial with patients with treatment-resistant schizophrenia. The next slide is now showing you the design of this trial. This is a trial design which we have agreed upon with all the European countries, with CHMP, with Canada. We've offered it again to the FDA, and they have generally no disagreement with this. It'll be a one-year study, placebo-controlled study. Very rarely do you get one-year placebo-controlled studies in patients with TRS. The first 42 days will be without getting medication, without randomization, just to make sure the patient is eligible. They're taking their drug. The plasma levels of whatever drug they were taking are adequate. An independent committee would decide which patient goes into the trial or not. Patients get randomized. After 12 weeks would be the primary efficacy endpoint. That would be the PANSS scale. Patients would continue after the 12 weeks on whatever medication they were getting. There is no choice decision to whether I continue or not. You're required to continue unless you're having severe side effects. At 26 weeks, we would have a second endpoint with, again, the primary efficacy variable would be the PANSS scale. If both the 12-week and the 26-week endpoints are positive, for Europe, we would no longer be required to do a remission relapse prevention study. That's a major benefit of this design, and the final efficacy assessment would be at 52 weeks. This is a study which we hope to get started in the second quarter of this year. I spent a lot of time, let me just quickly go through the remaining compound, which is Xadago. As Stefan has mentioned, it's already marketed everywhere. We, Newron, basically submitted the NDA and the European approval. It's globally licensed. We get double-digit, single-digit royalties depending upon the country and the geography. The next slide, which is slide 25, you can see the various countries where it is marketed in and all the partnering companies that have launched this product on the market. With that, I think I come to a close, and I turn it over to Stefan. Thank you very much for your attention. Thank you, Ravi. Fantastic presentation, and back to Alice for the Q&A session. Our first question comes from the line of Bob Pooler, Valuation Lab. Please go ahead. Thank you. Well, first of all, Happy New Year to you all. I think you guys are off to a flying start this year, and it looks very interesting, so good luck with that. Just a few questions from my side. Again, with the one-year results, and you had the interims before, what were the most surprising results of this at the one-year point for both of you? I think it's weird for me. I think probably it's the most scientific result. As I think I mentioned before, I fully expect patients who are doing well in schizophrenia for a period of time to start declining. That did not happen. I also never expected a responder rate to increase. Finally, the results on the number of patients who are no longer meeting criteria for treatment in schizophrenia, or the number of patients who have gone into remission, especially the remission. This just came out of left field. Never even thought about this. That's why we didn't even have criteria in the study to even consider remission. It's such a rare thing to see remission in patients with schizophrenia, and these are patients with treatment-resistant schizophrenia. Yeah. Irrespective of the results with evenamide, what it tells us is that basically, we're seeing a phenomenon that if you have a good drug, which is tolerated, patients take it, they seem to like it, you can get a very good benefit in patients with TR, even with TRS. If I may add, Bob, I think what was stunning to me is that, look, we are working with external vendors, everything is quality controlled. We have complete trust in the results that we got. Then you want to check it by external experts, by the opinion leaders. We had two meetings this year with those opinion leaders, one in Barcelona in October and one before in May in Toronto. The unanimous feedback by those KOLs is being completely stunned by those results and saying, "Well, if this can be confirmed by that coming pivotal study, that will really completely change the treatment paradigm in treatment-resistant schizophrenia." I love that even more because it tells us we are absolutely on the right path. Yeah, just the new phenomenon also, the patients in remission. What happens with those patients? Do they continue treatment or stop treatment? In general- Yeah, Bob, first of all Yeah in general, in schizophrenia, we tell always patients that even if your symptoms disappear, continue treatment for at least two years, three years beyond the point where you have no symptoms at all. Clearly, in a study, you can never assess that. In this study, the patients who are in remission, they were still on medication. Mm-hmm. Yeah, because you're also mentioning that there's potential for early access in the presentation there, too. The participants in the study, 14 and 15, are they continuing with treatment? Are you going to get Yeah further data from these? Yeah, I think we basically are continuing, the issue has been that we never designed the study to go beyond one year. we never even thought that, I personally never thought that we would be left with more than 20% of the patients. Fortunately Yeah we're left with about 80% of the patients. We have no time now to modify the protocol any further. We still have a few patients who are continuing treatment, but that's a very small handful. Okay, just on the second pivotal trial and sort of the first pivotal trial TRS patients to the Study 003. Could you provide a little bit the timelines there? I think you're starting- Yeah Q2 this year. Towards the end of the second quarter of this year. It will probably take us about one year to enroll patients, and then 12 weeks is the first primary endpoint, and then we need a few months for data cleanup, et cetera. Obviously, we would not wait till the full one year was completed before we would announce the results. Starting in 2024, we would go to mid-2025 and take the 12 weeks for treatment, another 12 weeks or so for data cleanup and all. By the end of 2025, beginning of 2026, is probably when we would have the results. Okay. 2025, 2026 results there. You mentioned that this trial, because I think from the previous sort of trial design, you've increased the number of patients there, and I think you're going from 10 weeks to 12 weeks now. Is that because this could also potentially be a pivotal trial? Well, it is a pivotal trial. Absolutely. Yeah. Okay. Actually, we initially designed it as a final trial. I mean as a single pivotal trial, because until now. Yeah The trial design is that you needed two. Yeah. In a single pivotal trial design, which has to be a design which the results are robust, the data are coming from a trial that is believable, it has to be for a condition for which there's immense medical need and no current treatment available. Those are the reasons. It's a substantially powered trial, and as you rightly said, basically, we increased the sample size dramatically. Mm-hmm. Just any read-through of this study that you're seeing on the upcoming Study 008 in non-TRS patients there? No, we're thinking at the present moment, the only thing I can tell you, we are very thankful the study got completed and the dropout rate again is very low. Okay. It's very low. It just signifies that whatever we see in one study is being magnified in the other study. Okay. Just on the outlying for there, the questions of when do you expect and what kind of agreement do you look at? Probably you will go for, well, you have cash I saw in the trial into Q3 this year. If this trial starts at the end of Q2, probably have a partner then, given that you need the funding for the trial before you start. Is that a correct assessment? Yes, Bob. You know that we have, generally, we have three paths. We could follow the example of Intra-Cellular Therapies. It's a wonderful example that against all odds, you just take the drug to your market. That leaves you with two paths. Number one is you finance this by equity, which I believe will be a challenge given our still current share price. The other is you go for a financing partner that is funding the development till the market and is repaid by future revenues, which is a very viable path. The second path is that you go for partnering, and you know that we have spoken about that once or twice before. That means we need either a global partner or we go for a staggered licensing. That means giving away Europe and Asia first, Latin America, and then after additional results, have the key upside, which is the U.S. and probably Japan, until the drug is ready for approval. That staggered approach might be the better one for our shareholders. Obviously if there's one of those global parties who says, "I want the global rights and I will expand this from being purely schizophrenia into bipolar and all the other cluster indications," which means that the market potential of the drug will increase from a blockbuster to a multiple blockbuster. Obviously would probably serve the drug best, even if our shareholders would only have one inflection point, but that would be without doubt a big one. The third option is obviously, we refer to that Cerevel or Karuna, obviously that's nothing we can plan, but we realize that can very easily be part of your life. For that, it's important that we have an independent board of directors and that the Swiss takeover rules are applying to us by our statutes. That's the three paths, the ones that we can plan for and the one that we are planning for, that's certainly the potential funding against future revenues versus the partnering a staggered or a global license transaction. Our next question comes from the line of Samir Devani with Rx Securities. Please go ahead. Hi guys. Happy New Year. Congrats on the data. It's a good start to the new year. I've got a few questions, perhaps just a couple or a few for Ravi, and then maybe one for you, Stefan. Just in terms of the trial, Ravi, can you just remind me, were patients allowed to alter their antipsychotic dose during the study? No. The patients were allowed minor adjustments, but if anybody basically needed a rescue, meaning greater than 20% in change in the dosage, then they were basically treated as a treatment failure. Okay, great. They had to be on a steady dose, in other words, basically. Yeah. Then, I think in your previous releases, certainly at the six-month time point in the presentation last year, you gave us quite detailed information on the various doses. Is it fair to assume that what we saw, the trends that we saw at six months in terms of the 7.5, 15 and 30, are pretty much replicated at the 12 months? Yeah, I think I would say probably they are fairly replicated, except that 30 milligrams seems to be becoming better with time. But again, it's nominal differences. I think at the present moment, I would say basically dose does not appear to be a major determinant of efficacy. It does look like, if you look at the example, LATUDA, there is only one dose which is effective. The higher dose is not effective, the lower dose is not effective. With antipsychotics, it's difficult to say. But at the present moment, I would say that if I had to pick, probably I would say that 15 and 30 milligrams are the best doses. Okay. Then, you are sort of guiding to the end of Q2 start for the phase III in TRS. Does that mean that you have technically had your end of phase II meeting with the FDA? Yeah, we have had a phase II. Is that? -meeting before. We actually have a new submission, which should be now with the new protocol, which will contain all the latest results. That should be again, the new submission now. We already have done that with the CHMP. With FDA, they needed to see the new protocol design. That's what we are submitting now. Okay, just one final one for you, Ravi. Just in terms of the design of the study and what you've updated today, in terms of the study remaining double blind, how easy is that to do? If you're going to announce 12-week data, whether it's positive or negative, how does that influence the patients on the double blind section? Is there a danger that the- Patients don't get to hear anything at all. Yeah, you're right. The way it works, it's a complicated story, but basically what it is that nobody excepting the statistician and a limited number of people would get to know the results. No investigator gets- At 12 weeks, you mean At 12 weeks data, sorry. No investigator gets to see the data. The team which is doing the analysis is completely new from that point onwards. It's like you build some kind of walls between the data- Yeah that has been analyzed and those who are continuing in the field. The patients, as far as they know, they were randomized to a dose, they're going to continue for the rest of the time period in the study. There's no break or blind. Okay. That sounds really complicated to me. Does that mean that you wouldn't put a announcement out after the 12-week analysis? We would probably do it under restrictions, and the full details would only go to a regulatory authority. Same invoices what we did with safinamide, Study 016 and 018. Yeah. 016 Yeah the pivotal, which was six months, Yeah extension of the that was two years, so that's what we did. Again, the full results would never be out. Okay. Just one for you, Stefan, just in terms of the partnering, you've gone through a few of the options that you're considering. I'm just wondering how much does the 008 study determine the path forward, because clearly, if you're looking to start the phase III, in TRS at the end of Q2, I assume that that deal has to be determined really pretty soon, you've got data coming at the end of March. Is it sort of the end of March to the end of Q2 is going to be sort of where everything's going to be happening? Yes. Samir, we are waiting for Study 008A, just to be precise, because we did have a study- Sorry, 8A. Yeah. No. Yeah. Perfect. What I can tell you is that the process with potential partners has been going on for quite a while. I can tell you that a substantial number of partners has been updated permanently, as we are speaking, our business development has informed everybody in the process about what we have disclosed today. There is going to be an opportunity, Ravi and I will attend to JPM in San Francisco next week. We have numerous meetings with interested parties to provide an update face-to-face. This process has been ongoing. Everybody is updated, to the extent possible. We are best prepared. Are there parties, the big parties, who want to see Study 008A results before they make the final steps? Absolutely. That is for various reasons. We don't have to discuss them in detail. It's necessary. Are there other parties who might not wait for those 8A results? Is it necessary to wait for the 8A results? No, because as you have taken from this call, one study in TRS, the pivotal study design that Ravi has just presented, which will be a gold standard study, 12 months double-blind placebo-controlled study in TRS, one study would do. What is the requirement for this Study 8A? Well, we obviously want to see supportive results for a filing in Treatment-Resistant Schizophrenia. Is it a must that these results are fully positive? No, not at all. Is it relevant? Oh, yes. Sure. If somebody would go for a deal ahead of those results, would he discount the payments or make it in milestones? Absolutely. I think that is, to describe it in a lot of complexity, what might happen. Are we confident that the process might be very speedy once those results are out? Absolutely. That's great. Thank you. Everybody is up to speed. Okay, perfect. Maybe just one final question. Just in terms of the finances, you've talked about cash to sort of Q3. Yeah. Does that include any repayment of the EIB loan? I can tell you that we have very good discussions with the EIB. Even if there is nothing declared yet, we are confident that there will be no repayment to EIB in June. Okay. Perfect. Great. It will not be an issue. Okay, perfect. Thanks very much. My pleasure. Thank you for the questions. Our next question comes from the line of Leonildo Delgado with Baader Helvea. Please go ahead. Hi, everyone. Happy New Year and congrats on the results. I have a couple of questions on evenamide and a couple on your partnering efforts. What are the key risks do you see in the phase III in TRS? Hello, there? Ravi? I'm sorry, could you the question again? What are the key risks do you see in the phase III in TRS? In the phase III, the key risk? Yeah. Well, the first risk, I think in any antipsychotic is basically that the placebo response can kill the study. As you saw, the Lundbeck compound was a very well-designed study that placebo response killed it. We have taken a few precautions here. There are differences in the design. They chose a design in which they made patients respond before they randomized them to placebo, and they expected the placebo group to get worse. We have done the opposite. We have taken patients who are not doing well, and we are excluding all patients who have done well during the screening period. We only have patients left who are not doing well, who have failed. Hopefully this will reduce it. Secondly, we have a duration of treatment which is very long. As I said just before, placebo response doesn't usually last that long. The fact that we have 12 weeks and 26 weeks and 52 weeks, I think if a placebo could last that long, it should be marketed. I don't expect the placebo response would go that long. That's the second thing. Third, these are patients who have failed drugs, at least two, based upon the international TRRIP criteria. These are pretty hardened patients who generally do not respond to the placebo. Those are the things we can do that's for placebo response. Second is an unknown toxicity. Kind of unlikely because we have more than 500 patients treated, but theoretically, you could never say no, that it won't happen. Third, which I think is what makes me most nervous, is the idea that we could have another pandemic. That would be something which we cannot do anything about. Those are the three things that I see at this stage. Okay. Thank you. Do you have any insight on the potential pricing of evenamide if it reaches the market? I think what we can say, Leonildo, is that the pricing is never the decisive force in the sales of those antipsychotics. Where they really get the billion-dollar sales from is not an excessive pricing, but it is the huge number of patients that will be using the drug. We would certainly advocate that the pricing should be supportive of a huge and fast spreading in the market of this compound. Don't forget, we would be the one and only treatment alternative to all those 30%-50% patients who are treatment-resistant and have to take clozapine, but don't want to take clozapine. We would be in a fantastic position to penetrate that huge market very quickly, and that is the discussion we're having with the partners. If it should be globally licensed, then as you know, the final pricing decisions will be taken by the partner. Mm-hmm. Thank you. Maybe the next one goes to you, Stefan. You already said it, conversations are ongoing, partnering conversations. Yes. I'm just wondering, what has been the feedback of your potential partners so far, and what's their profile? Are we talking about big pharmaceutical companies, mid-size? Could you shed some light here? Oh, the options are widespread. We have global partners looking for these results from Study 008A to confirm their interest. We have regional partners who want to see the results or who are willing to discuss, and we have territories like remote territories, parties who want to have the local rights only. We are in the luxurious position to have competitors or, let's say, interested parties for all types of deals. We are talking to parties that are interested in funding studies. In the best case, we can pick the best option for our shareholders and the best option for the patients and the largest penetration. That is something that we enjoy. Let's see in the next weeks where that takes us. Okay. Maybe just one final question. As you just mentioned, cash runway goes into 3Q. Yep. So- Q3 We all know Q3. Exactly. We all know that sometimes partnering conversations tend to take longer than expected. Yep. I'm just wondering if there is any fallback plan in case it takes longer or beyond- Absolutely Q3. Yes, absolutely. You can rest assured that this company will not run out of cash because two or three months of cash are missing. Discussions are ongoing. It is clear to us that our shareholders are very sensitive about dilution, there will probably not be a material fundraising of material dilution because, quite honestly, the cost of the study and the cost to the market would be too much dilution to bear, it is not a valid option for us. If there is a need for two or three months or six months additional cash runway, we'll understand that this company protects the value of its asset, of its key asset, especially in the case of positive results. None of the parties that we are talking to should speculate on Newron running out of cash. I guarantee. Great. Thank you. My pleasure. There are no more questions at this time. Back to you for closing remarks, gentlemen. Thank you everybody for attending the call. It has been a huge pleasure to start the year with this news. I can promise there will be more news to come very soon. Stay tuned. Talk to you next time. Have a good rest of day