Newron Pharmaceuticals S.p.A. (NWRN) Earnings Call Transcript & Summary

Ladies and gentlemen, welcome to the Evenamide One-Year Results Conference Call. I am Sandra, the Chorus Call operator. [Operator Instructions] The conference will not be recorded for publication or broadcast. At this time, it's my pleasure to hand over to Mr. Stefan Weber, CEO of Newron Pharmaceuticals. Please go ahead, sir.

Thank you, Sandra, and good afternoon, everybody. Good morning to those, who are listening to us in the United States. It's really feeling good to be back again to you so soon after a call on January 3, we are ahead of schedule with those results from the first 100 patients suffering from treatment-resistant schizophrenia, patients who have added evenamide to their current medication and who are staying on track for 12 months period. This is just to put it in perspective, only the second milestone of minimum 5 or 6 relevant milestones that we are going to disclose this year on this compound. So it's a good reason for you to stay tuned. The results we are going to present to you and explain to you today, we present what in our first call this year on January 3, when we look at the 6 months results, being asked about the potential scenarios for 12 months we call the blue sky scenario. What we show to you today is an almost flawless safety profile. We're showing to you an unexpectedly high number of patients, who completed the 1 year of study duration. We show to you to the extent applicable statistically significant improvement versus baseline on all efficacy endpoints. We are proud to show that the improvement seen in patients is continuously working in the right direction after 6 weeks, 6 months and now up to 1 year. It's a continuous improvement week by week. And very proudly, we can also say that we have a drug that is showing an ever-increasing proportion of responders, which, for example, sets it apart from clozapine the magic drug, which knows responders or nonresponders from day 1 on. Our drug seems to turn nonresponders into responders by high numbers. But before we get into all the details, let's do a bit of housekeeping. So I'm on this call today. I'm joined by Ravi Anand, our Chief Medical Officer; and Dennis Dionne, our Vice President for Commercial Affairs. Ravi will join me to the presentation, and Dennis will join for the Q&A on any questions on commercial positioning and market. The slide deck that we are guiding you through today has been downloaded or can be downloaded from the website. I will advise you that we had 2 minor glitches in the first version this morning at 7, which we have corrected. We will guide you through that slide deck. And there will be a replay of this call on our website later tonight. So let's get started and allow me 5 minutes to guide you through for those who have not been joining us lately, what Newron is all about. If we go to the first slide of the slide deck, Newron is all about CNS drug development, and we are looking for compounds that come with whatever kind of exclusivity and our long-term strategy is that we should sell our drugs ourselves, at least in some territories or in some niche indications. We are listed on the Swiss Stock Exchange since 2006, our shares can also be traded on the website. So you should carefully watch out for the disclaimer on Slide 2. Our portfolio, I would say, consist right now of 2 crucial compounds. The first one is Xadago for Parkinson's disease, that was a drug around, which Newron was created. And all that you should keep in mind is that we took this drug over all the development hurdles and the regulatory hurdles, and we brought it to the market ourselves in the European Union, in Switzerland and the United States. So for whatever you want to -- credit you want to give to us, we know how to take drugs to the market and our Chief Medical has done it with other companies before. And the other thing I would like to mention is Xadago, which was the first new chemical entity in Parkinson's being approved in the U.S. and Europe for more than a decade. So there is innovation in here, it comes with the same kind of mechanism to a certain extent as evenamide. I will come back to that in a second. The second thing we know about Xadago, it is a very safe drug, which it again seems to have in common with the evenamide. So talking about evenamide, this is really the trigger deliver for the increase of value for our investors and shareholders, because this combines a new mechanism of action and the new positioning with a long patent life in schizophrenia, both nontreatment-resistant and treatment-resistant schizophrenia. So we know how to take drugs to the market. We have a portfolio. We are about to add additional compounds to that pipeline that strategically make a fit. And we are sufficiently funded to complete all the studies that are ongoing and that money that we have in the bank and that we are cashing in [indiscernible] R&D tax credit will take us at least to the middle of next year. If we go to Slide 4 that shows you the pipeline, and there's just 2 things I want to mention here, and that is that all the 3 compounds that we are currently having in the pipeline go back to the origin Newron. It's all about sodium channel blockers. Now you know sodium channel blockers are very efficacious class of compounds, many have material side effects and have been killed on the way to the market. So it is very important that you know that we are looking at a subclass of sodium channel blockers, which we call voltage-gated sodium channel blockers. These drugs only work if, when and to the extent needed, and they leave the basal levels of neurotransmitters intact, which is very important, so we get the benefit, and we do not get the side effects. And the second thing that we claim to be innovative is that everybody else would develop these drugs in epilepsy, while we have taken them to Parkinson's disease, into schizophrenia and central pain indications. In Parkinson's, our drug is the one drug that has a dual mechanism of action. It's a MRB inhibition, which improves Parkinsonism and the glutamatergic arm of the mechanism is reducing dyskinesia. In evenamide, the glutamatergic arm is the key to all those patients, who are no longer fully responding to their medication or who are treatment resistant. And in pain, it is the key to central pain indications. Going on to Slide 5, we are now on evenamide and let me give you a nutshell what this is about before I hand over to Ravi. There's no doubt that schizophrenia is a large market. We are talking about 1% of the population in the world wherever you go. It's remarkable that at that 1%, 30% to 50% of patients will be called treatment resistant. If you go by the strict regulatory definitions, it's probably more than 30%. But any doctor you talk to would say, at any given time, he could qualify half of his patients as being treatment-resistant, means not responding to at least 2 different compounds anti-psychotics approved on the market today from 2 different classes. What is unique about evenamide is the mechanism of action. It is a glutamatergic mechanism. We are not targeting dopamine. We are not targeting serotonin like each and any of the other drugs, we exclusively target glutamate and we do it in a dose-dependent way and we leave the basal glutamate completely intact. And that is why we have defects, but not a side effect. The second key differentiating thing is the positioning. Our first indication is we go as an add-on therapy. In each and any case, evenamide will be added to each and any of the current first or second-generation antipsychotics. The key advantage is that we can turn nonresponders and to responders without having to take patients off their current medication. No relapse risk, no hospitalization, no risk of increased suicidality. Our patients just stay on their current medication and get additional benefits, no incremental side effects. Very convenient, very safe, very good for the doctors, the patients and the system. The second differentiating feature is that we are the one drug that is going for treatment-resistant schizophrenia. You know that currently, there's only clozapine and that is 35 years. And you don't know that drug is quite magic in its efficacy, but it's potentially disastrous in its side effects. And that is why 90% of the U.S. patients who are treatment-resistant schizophrenics will not take the only approved drug for this, clozapine, and 80% of Europeans who are treatment-resistant will not take the only approved drug clozapine. That means everybody else will be given whatever the doctor believes, gives some benefit with patients or silence in whatever the intention is. This is a huge population and evenamide is the 1 drug since clozapine that seems to work given today's data in a magnificent way in treatment-resistant schizophrenia. What we can show to you is positive results from a Phase II study in non-TRS patients, the first indication and the first of 2 pivotal studies to get this drug approved is already ongoing in the non-TRS indication, and we expect results later this year. Until last year, you could have told us, look, your claim in TRS, that's nice, but you have nothing but the mechanism and everybody agrees that glutamate seems to be the key to TRS these days. But the only have some mechanism and you have some animal data ,show us patient data. And here we go. We have the first 100-patient interim results for 6 weeks. and 6 months. And today, we have to 12 months interim results for those 100 patients. These 2 pivotal studies being successful to get the drug approved in overall schizophrenia. But there's a fair chance that in TRS one study would cut the pie and before we get the formal approval, there's a chance for any market access, including reimbursement in some key territories like the U.K. and France. While in other territories like the U.S., the early access would only be the instrument to collect additional safety data. The drug comes with an exclusivity from composition of meta patents, which is up to 2033, that's global and in Europe and European Union, as you know, we have the 10 years exclusivity and that applies from the year on when the drug is approved. That all said, I'll hand over to Ravi to guide you through evenamide in more detail and the exciting results we have seen today.

Thank you, Stefan. Good morning to all, and good afternoon to those in Europe. So I'm on Slide 6. What I'm really going to talk about is the science part of the presentation today as a data. I think Stefan has already mentioned about the size of the population. I think the WHO estimate is 1% of the competition, it is below a out in the low. It does not -- schizophrenia is a disease that basically is an equal opportunity of gender; whether it be male, female, any race, the prevalence is approximately the same. Schizophrenia is a very vast population of patients to be treated, because the onset of the disease in males is around 16, 18 years of age, in females approximately 5 years later, and the disease does not die out. Patients will still have the symptoms of the disease, although maybe not as severe bill in the 170s. So you're looking at basically 30, 40, 50 years of medication intake. Schizophrenia is a disease that destroys not just the patient at the best time of their life, it affects their educational attainment. It affects their ability to work. It affects the social functioning and it's also devastation for the family. Needless to say, the cost of schizophrenia to society is enormous, it's in hundreds of millions per year in the U.S. There are a lot of drugs available for the treatment of schizophrenia. And depending upon the country, generally, you have about 25 to 30 antipsychotics that are available. Most of them are generic. But in the last few years, we have had 3 or 4 new drugs, which are available. The discovery of antipsychotic treatment is linked to the assumption that dopamine is a cause of schizophrenia. Dopamine blockade will produce benefit. And to a certain extent, the second part of the statement is correct, dopamine blockade does produce an amelioration of symptoms. However, we now recognize that over time, this blocking becomes ineffective. And actually, we may contribute crippling symptoms such as that dyskinesia, weight gain, sexual dysfunction, hormonal imbalance. But at the same time, work done using magnetic resonance spectroscopy, positron emission tomography, identification of patients who are at risk for schizophrenia that don't have it just yet have identified something which is very interesting and relevant to our discussion today. In patients who are at risk, patients who are having the first episode of schizophrenia, what we see in the brain is an outpouring of glutamate, not dopamine. And this glutamate seems to trigger to the illness. Although most patients with first episode of schizophrenia respond well to medication. There are about 10%, 20% of patients who in their first episode already do not respond to medication. Over time, at least 30% of the patients will not respond to the dopamine serotonin blocking product. And we now begin to realize, based upon work done in different hospitals and universities that patients who develop resistance to retreatment or who are resistant right from the beginning, they have an excess of glutamate in their brain, but no dopaminergic abnormality. Whereas there are patients who respond to dopamine blocking drugs, they have no glutamatergic abnormality, but we have increased dopamine sensitivities. The patients who become treatment resistant. Like I said, some of them are right from the beginning, some over time. The conventional and scientific definition of treatment often schizophrenia at the present moment is that these patients fail to respond to at least 2 different antipsychotics given an adequate doses for an adequate period of time in 30 -- more than 30% of the patients who are treatment resistance and probably around 60% to 70% of the patients, maybe inadequate responders as has been demonstrated in the NIMH sponsored CATIE study. If you go to Slide 7, what we have recognized is the fact that at the present moment, evenamide is the only drug in development for the treatment of patients who show inadequate response. This inadequate response could be in patients who are not treatment resistant, but on their way to go in there or it could be patients, who are treatment resistant and don't respond. So if we're looking at 2 different indications for this drug. The first would be for patients were earlier in the illness, but are not responding well. They show some benefit, but not a lot. And even after the treatments have been given, they show symptoms of psychosis which are persistent. This is a very large population. The second indication, which is the one that has really fascinated us is treatment-resistant schizophrenia. Schizophrenia is a crippling disease, I have mentioned before, which shortens lifespan by about 10 to 20 years. But treatment-resistant schizophrenia is a horrible, horrible condition. Patients are much more at risk of suicide and much more at risk of hospitalizations. We have repeated hospitalizations, we have breakthrough psychosis. They are frequently the victims of violence. And there is no treatment for them. In 1988, '89, we were very happy to have clozapine, the first drug that would show benefit in these patients. about 30% of the patients in the pivotal study responded. But the vast majority of patients do not show much of a response to clozapine or very inadequate response. The 30% of patients who do respond to clozapine, unfortunately, lose their efficacy over time. And secondly, those patients have to go through very stringent monitoring requirements and the side effect risk of seizures of sudden death, of agranulocytosis, other blood dyscrasia is very high. And therefore, they need to have blood test done for a very long period of time, almost at weekly intervals, which schizophrenic patients don't like. And they don't take it. And as Stefan mentioned, in the U.S. is about 5% to 7% of patients who take clozapine or those who are treatment resistant. Europe number can range from 10% to 17% of those treatment-resistant patients taking clozapine. There have been attempts to improve the efficacy of clozapine by adding on drugs and not a single study has proven benefit in an adequate number of patients. So we move on to Slide 8. And why is it that we think evenamide is going to benefit. This is what we call as a voltage-gated sodium channel blocker. In other words, what it does is, it becomes active only when fluctuations in the voltage require it be. So on the first slide -- sorry in the first panel, as you can see on the left-hand side, if we consider the dose of -- on the concentration of evenamide that is required to produce an effect in major sodium channels in the rat cortical neurons is 25 micromolar. That will be buckets and buckets of the drug. However, in the inactivity state of the channel when it's not working properly, the only required point for micromolar. So the drug seems to know when it's required to [indiscernible] and when it's not. And this is best reflected in the middle panel, where you can see a high frequency firing neurons. These are the neurons that are troublesome. These are the ones that can cause seizures. This is what happened in schizophrenia. And you can see that the control condition has no effect. But at 1 micromolar evenamide completely wipes out all the high-frequency firing neurons. The low frequency firing neurons, which we all need for functioning are unaffected at this concentration. Why is this important? Because there a lot of sodium channel blockers on the market, carbamazepine, Tegretol, that is -- these drugs are effective antipsychotics, but they block all neuron firing indiscriminately. And that's why you have the severe neurological side effects with these drugs. Because evenamide does not affect normally firing neurons, the hope and the data to this date indicate it would not have this propensity. How does this drug work? And this is the last panel shows you an experiment, which we call as in vivo microdialysis, in which we put a pump and a probe in freely moving rodents, and we look at the effect. With the glutamate system, one thing is very important that we should not disturb the system in its normal state. In other words, basal glutamate should not be disturbed. If you do that, you're going to have psychotomimetic side effects. In other words, that effects that mimic psychosis. I mean this graph, you can see the first part of the line, which is flat that's the basal glutamate, and there's no effect of evenamide on it. Where it shows the arrow basically, what we do is we actually give a drug, a sodium channel pour opener, and there is an outpouring of glutamate, which is a black spike that you can see. The blue and red spikes basically are dose-dependent inhibitions of the glutamate. This is the only thing this drug does. Out of the 130-plus neurotransmitter enzymes, transporters that we've examined even in concentrations of 10 micromolar, and this drug is directed at 0.4 micromolar. We have no effect on any of the systems. So this will not affect the other systems. It will not produce sedation, it will not produce sexual dysfunction, it will not produce at can, no extrapyramidal symptoms. Going on to Slide 9. From the in-vitro work we moved on to in vivo work and these are the various models that we have done in that. Schizophrenia, if it was to be diagnosed -- to be described today what we call a cognitive disorder and not a behavioral disorder. Every patient with schizophrenia has severely disturbed cognition. One of the fundamental defects in schizophrenia is information processing, and we have looked at that in a very exhaustive way. We have looked at all the animal models of schizophrenia. And whether we look at monotherapy or as an add-on therapy, evenamide is successful in reversing the damage done by the -- in the experiment. The advantage of add-on therapy is that what we see is that the dose that is required for line evenamide to produce the benefit in an add-on situation is far lower, which suggests 2 things: a, it will have lower the dose of randomize for sure. But more importantly, seems to suggest that the drug to which we have added on is contributing something to the efficacy, which allows the evenamide dose to work. So in other words, there's some degree of synergism or additive benefit. If you go on to Slide 10, this is a summary of the data that we have safety data at this point, and we have approximately over -- fairly at the moment closer to 500 human subjects who have been treated. The completion rate in all studies is very, very high. We have 160 healthy volunteers, who have received single doses of 60 milligrams without any side effects. The side effects that we described are trivial and the same incidents as in placebo. We have about more than 270 patients with psychosis, who have been treated and as you can see, they have very few side effects. Somnolence, headache, insomnia, which is generally mimicking the same rate as in placebo. So we have 275 patients, who have completed overall and about 130 patients, who are ongoing in the extension studies. Again, only 4 patients have dropped due to side effects and 20 for withdrawal of consents and inability to end the clinic visit. So the conclusion on Slide 11 is basically the drug is very safe, even up to 60-milligram single dose. We have by now given 30-milligram multiple doses to patients, 30-milligram BID, I should say, to patients and in over 100 subjects and there are no side effects. We have done a QTc study showing no increase in QTc compared to placebo. There's no EPS, there's no metabolic syndrome, sexual dysfunction. There are no CNS side effects that we note of and there are laboratory abnormalities. So this profile is extremely important, because it suggests this drug would be safely added on to any other drug or any other drug could be added on to evenamide. Moving on to Slide 12. Just this is to describe the background study, which we did a few years ago. This was a placebo-controlled study done in the U.S. and in India, a very small study in 89 subjects. But in this very small study where we took patients, who are on risperidone or aripiprazole and who are beginning to show symptoms of return of psychosis. The addition of evenamide produced significant benefit. On all the measures, you could see a benefit statistically significant was on the PANSS positive, which is exactly what we wanted to control and on the responder rates. But we also saw benefits on the clinical global impression of change and on nonsignificant benefits and all the others where it seems to be a function of the sample size needed to be larger. So now we come to Slide 13, which is the regulatory interactions page. We have defined 2 indications for further development and that's been discussed with extensively in the European authorities, a list of countries, including EMA. And we've also discussed obviously with the FDA and with the Canadian authorities. There will be 2 indications, as I mentioned before, and following discussions with them, the additional work requested by them is nearing completion or has been completed. The preclinical work has been completed and submitted to the FDA. And the first 4-week study, which was looking at EEG has been completed without any adverse findings. By now we have more than about 100 patients preceded in different studies of the drug probably 120 or so. And we will address the remaining clinical issues. We will be happy to address now in Study 14. And once these final studies also way written up, we will be submitting to the FDA, hopefully in the second quarter of this year. So now I come to Slide 14, just the focus of attention today. This was a study, which we initiated a few years ago when we realize that we do not have any data on the use of a glutamate release inhibitor in patients with treatment-resistant schizophrenia. Although our hypothesis is that this could benefit the drug -- of the patients, there is also evidence that glutamate antagonist could actually cause severe significant worsening of patients. So before we got into a full-blown pivotal study, we wanted to do a pilot study, which we would add these drugs under conditions in which the investigators were very comfortable dealing with patients. And therefore, we derived a randomized study in patients being randomized to 7.5, 15 and 30-milligram BID of the drug. As an add-on, in patients with tickets schizophrenia meeting the conventional and the international criteria for treatment-resistant schizophrenia where they will be taking any drug except clozapine. And this study was an open label, but with black iterators to enable the rating of the dosage effect to be blind, but the principal investigator was having full knowledge of what the patient was getting so they could monitor safety. The patients were all psychotic. They have met the criteria score of the PANSS, which is a positive and negative syndrome scale of greater than 70. CGI, Clinical Global Impression of Severity for patients with moderate to severe, very severe patients were excluded because they need to be hospitalized. The study was an initial period of 6 weeks. And then for those patients, who wanted to continue based upon benefit or the lack of side effects, they will continue on for another year. We randomized 161 patients and the primary outcome measures were the PANSS total score, which is the same as what is required by every health authority for an approval of a drug, and I'll go through the initial results later. Moving on to Slide 15. The objective of the study was preliminarily -- the primary objective was to look at safety and obtain preliminary evidence of efficacy. It has completely overseen by an independent safety monitoring board and international one to make sure that there was no sustained risk to patients. All the analysis, which we have done are based upon a last observation carried forward. So even though patients may drop out for any reason, their scores a carried forward. This is the more conservative analysis to be done, and that's what we have done. So what you will see here are the results. And because the study is still ongoing, we have not unblinded by dose -- but what I can tell you is that in the first 100 patients that we'll be presenting results of, the majority of the patients are on 7.5 and 15-milligram BID and only a handful are on 30 milligrams. The reason being is as time when the study was initiated, we first started with 7.5 and 15 milligrams. And following an analysis done and submitted to the Safety, Monitory Board 30-milligram group was allowed to be randomized into the study. But unfortunately, at that time COVID hit. And because of COVID, enrollment slowed down tremendously. So if you come to Slide 16, what happened is that basically the -- we managed to get the first patients randomized by the fourth quarter of '21. And then because of COVID, enrollment completely slowed down, but the patients were continuing long term. And the Safety Monitoring Board felt that it will be unethical to continue treating patients long term unless there was some evidence of efficacy. So they asked us to do a blinded interim analysis and which we did. But of course, since this was not expected to do an interim analysis for efficacy, it took a long time to get everything set up, and that's what we presented last year at the CINP. Now the 100 patients that I mentioned were randomized in fourth quarter '21, the last 61 patients, we were only able to get into the study by sometime in November of last year. So you can see there's an extensive delay and mainly the reasons were, again, COVID-related center shutdown, governments didn't review protocol, didn't review amendments, investigators moved, travel restrictions, et cetera. So the 6-month data we were able to do much faster and they were presented in January, the beginning of January. And by the time that all the patients have completed 1 year since the statistical analysis plan and the procedures were set up, we were much faster with the 1-year data, which was basically collected by 20th of January, and we are releasing today. So as you can see, our ability to handle data is pretty quick and provided, of course, that we had some advance notice of what we're doing. So with those comments, let me go on to Slide 17 to describe to you what happened. So the first 100 patients who were randomized, at the end of 6 weeks, 97 patients completed 6 weeks of treatment. This is virtually unknown that in treatment -- in schizophrenia to have such a high completion rate, especially in treatment-resistant schizophrenia to have such a high completion rate. Of the 97 patients who completed and were the option to continue, 90 patients chose to continue treatment. Why do I mention this number because this implies 2 things: a, firstly, the drug must be very well tolerated because otherwise, patients will not continue. Second, they must be seeing some evidence of benefit, because schizophrenic patients are notorious for switching over. It's not just a patient, it's the caregiver who has to bring the patient to the clinic repeatedly. So they must have seen some benefit. Of the patients, 90 patients who entered the extension for the 6 months period, what we realized is that only 85 patients completed with 5 dropping out. Of these patients, 7 did not enter the extension any further. And so we have -- of the 85 patients 5 discontinued and then we have 77 patients, who were at the 1-year mark basically entering towards that and a total number of 8 discontinued. Adverse events were only 2. 2 patients dropping out due to adverse events, as you can see at the bottom. And these were one patient who had a flu-like syndrome. And the second patient were a combination of dizziness, loss of concentration, headache, et cetera, nothing consequential. Mostly patients withdrew because they didn't want to have any more visits. There's too many visits coming up and some are lost to follow up during the COVID period. Moving on to Slide 18. So the efficacy measures involved in the assessment here, and they are the same ones as we have in every trial in schizophrenia. So there's nothing no surprise out here. We made sure that the psychiatrists, who were rating these were trained to an internationally acceptable standard. So we have the PANSS scale, the Clinical Global Impression of Severity, the Clinical Global Impression of Change and the level of functioning scale, which is known as the Strauss-Carpenter scale. Slide 19, a slight repetition, but just to clarify the numbers again. We had, like I said, 100 patients, who were enrolled, 98 patients who took the medication and subsequently came for at least 1 post-baseline visit. This constitutes what the FDA and under ICH we call it the modifying interim to treat population. 97 of these patients were completing. At 6 months, we have 85 patients were completing and at 1 year 77. The definition of completion doesn't mean the necessarily they are taking all till the last day. It means that they have completed that period of observation in the trial. So now we will be talking about what is the moderate, what is severe and what is mild. So we go on to Slide 20 and give you 3 examples of symptoms and how we did it. Let's take, for example, delusions, which is a both commonest symptoms in schizophrenia without which you can't even really make the diagnosis. Delusion basically is a very falsely held belief that the patient absolutely believes in it. There could be absurd things like I'm invincible, I'm the strongest person. I'm the king, people are pursuing me. When we say give a rating of 4, which means moderate. That implies that some of these things are present, but they're quite well formed and they do interfere with the patient's thinking. A rating of 6, which we use severe would be -- completely interferes with functioning and the patient has very elaborate contrived explanations to why he thinks the neighbor is listening to him through the wall. And the 2 would be mild or questionable, which would be very questionable pathology. Similarly, conceptual disorganization, which is a big word for saying disorganized way of thinking, you could think in terms of Donald Trump. That will be a 4, would will be when the -- becomes unable to deal with complex communication and goes under tangents this way or that way. A 6 would be when the patient cannot complete a thought process because of almost a complete disruption of what he was trying to say. And 2 would be there's almost disappeared by that time. Hostility is easier to explain. 6 would be patients who indulge in assaultive behavior, could be severe anger or resentment. 4 will be an overly hostile attitude. We could shout at people, frequent irritability and 2 would be rare, sometimes there, sometimes not. So with these, we now go on to the results of the study, Slide 21. This is the positive and negative symptom scale. At baseline, these patients had a mean score of about 80. This is a mean score of 80, while they are on an antipsychotic. If the antipsychotic were not to be there, it probably would be approximating 90. These patients are on antipsychotic. We added evenamide and at 6 weeks, the score dropped to about 70. That's quite a good achievement, but it doesn't say that we were on fire. This is a modest improvement in patients with treatment-resistant schizophrenia. And at that point, the thinking was that this could very well be a placebo response, because patients with schizophrenia and do show significant placebo responses, even those with treatment-resistant schizophrenia. We went down to 6 months fully expecting that the patients whose scores that had dropped probably would go back up again, like, a 6 months placebo responses doesn't last. But to our surprise, the mean scores improved further compared to week 6 by 30%. And furthermore, when we looked at patients at the end of 1 year, they have improved by another 50% compared to week 6. These changes are significant compared to baseline. The pattern of improvement -- it's not that this is a eureka moment where the patient drops by 20%, 30% in 1 day or 1 week to a very gradual slow improvement, but steady. Of course, these are the mean results, which means for the whole population, which disguises the fact that whether maybe some patients are included, others or not. So what we do is we always do what is known as a responder analysis. The responder analysis is showed on Slide 22, where we look at the proportion of patients who improved by a clinically important magnitude, and that is similarly defined as 20% in patients with schizophrenia. At week 6, it's a very modest 16% of patients. And when we get to week -- to 6 months, you can see that the responder rate, which is the light blue, has more than doubled. And at 1 year, it's approximately tripled. Now this is fascinating. No study, to this date, has shown a significant increase continuing on the responder rate up to 1 year. With clozapine, we have seen results where clozapine patients improved at 6 weeks. They improved further at that 6 months published study shows that and the magnitude of improvement in 6 months is more or less what we are seeing with the evenamide here. But the number of responders to clozapine do not improve over time. So this is a result which we are seeing, which is, in a way, fascinating and intriguing because, not only this implies that the patients who had improved initially continue to improve, but more importantly, especially because this is treatment-resistant schizophrenia, patients who did not improve initially must have improved a lot. We're having more and more patients who are responders. In other words, there's hope for patients who do not improve right away. And what fascinates us is that the fact that at 1 year, we have patients who have not improved at 6 months are now converted into responders. So not only do you have an improving benefit, you have a clinically relevant increase in the number of patients who have the benefit and the benefit itself. This is a measure, the PANSS, which looks at the symptoms of schizophrenia, 30 symptoms, and, of course, it's driven by scale. On Slide 23, we have another measure. This is the clinical global impression of severity of illness. Here, the psychiatrists, with a lot of experience with the patients, looks at each patient, talks to the patient, considers how they are dressed, how was their orientation in time, do they still believe that they are not sick, that somebody is bringing, forcing them to come in, do they still believe that the world is flat, do they still believe that they should be in politics, et cetera. They look at all the symptoms. It's a holistic assessment for the patient. And a score of 4 generally means patient is moderately sick. A score of 6 means patient is severely sick. A score of 3 would mean, basically, patient is mildly ill. We started with a score of 4.6, which is meaning, basically, that they are between moderate and moderately severe. At the end of 6 weeks, they had improved to a mean score of 3.9, which means just below moderate, so they are mild to moderate. And at 6 months, again, the same pattern repeated, that there was a 25% further improvement compared to week 6. So the initial improvement, which could have been a placebo response cannot be a placebo response at 6 months. Again, it's gratifying to see that at the end of 1 year, the severity of illness, not just the symptoms, the overall severity of symptoms, severity of the disease, the psychiatrist rated as being at least 50% better than compared to weak 6. These differences compared to baseline are statistically significant. And this is, again, something which is very unique. It's common to see an improvement in severity at 6 weeks, just so at 6 months, but at 1 year to hold off on an improvement in severity, continuing further, is mainly infrequently noted. But again, that was the mean. Now we have an analysis on Slide 24, which is the -- looking at each individual subject and only considering those patients who improve to what we call as very much improved or much improved. So these are the 2 top categories. Generally, in studies, we look at any improvement, even if it's mild. In this case, we decided to look only for this very much in margin, ignore trivial improvements. And as you can see at the week 6, it's a very small percentage, about 10% of patients. About 6 months, you have increased by 50% compared to the week 6. And at 1 year, they more than doubled compared to the 6 weeks. Again, the same pattern as you see in the CGI of severity mean, the PANSS, the PANSS responders. With time, the proportion of patients who improve keeps on increasing, and the overall severity of the population keeps on decreasing. We have another measure, which is called the CGI of Change, Clinical Global Impression of Change, which is on Slide 25. In this, psychiatrist is assessing the patient to see how is compared to when he came into the study. Is the patient the same, which would be a rating of 4; is the patient better, which would be rating a 1, 2 or 3; or is the patient worse, which would be a rating of 5, 6, or 7. So we here considered only those patients who are rated as very much improved or much improved, ignoring the trivial improvements. At week 6, about 1/4 of the patients met this criteria. At 6 months, it had increased by another 30% and in 1 year, by 40% compared to weak 6. So once again, we see on this measure, the same pattern as we saw before, of increasing response slowly over time, but clinically important benefit -- and the clinically important benefit is characterized by responders increasing over time. And at Slide 26 is more humor than anything else. It's just to show you and it's barely visible, but if you look at the 1-year mark, you will see a slight yellow dash at the very top. And that indicates very much improved. So even in this group of 100 patients, we have a patient who has improved, but very, very few patients ever improve by very much. So gratifying to see that over time, the category of improvement is better and better to such that the psychiatrists, who are trained psychiatrists in these cases, say that the patient is very much improved. Last but not least, Slide 27, which is looking at the level of functioning. The objective of treatment in psychosis, patients with psychosis is ultimately to improve their functioning. These patients are totally dependent upon somebody else for their care. And if the symptom improvement, the severity of disease improvement was not to be reflected in functioning, then it's not much use. Functioning is what you really want to improve in this patient, so they can do some things for themselves. And this is a scale which is looking at the symptoms of the various aspects of functioning. And what we are seeing here is again, a slow, gradual improve over time. And this sort of solidifies the picture of a drug which is doing something which is symptom-wise improvement, severity-wise improvement and on functioning. So it's a complete package. So moving on to Slide 28. I think I've basically, more or less, gone through all these things. I will not repeat it. But what is fascinating again is to see the 77% of the patients completing 1 year of treatment. Again, this to, me is very critical because this suggests great tolerability and there must be a benefit, which we have, I hope I've shown to you in the last few slides. Where do we go from here? On Slide 29, we have 2 potentially pivotal studies to perform to meet the NDA and dossiers, requirements. So we have the first study that's ongoing. This is a study in patients who are not treatment-resistant, but are inadequate responders and on antipsychotics. This is a 4-week randomized double-blind placebo-controlled study. It's going on in a bunch of countries, we expect that we will be able to complete enrollment this year and bring the results by the end of the year. A total of 260 patients will be enrolled in this trial. The second study will be the first placebo-controlled study in patients with treatment-resistant schizophrenia who are on an antipsychotic and not benefiting from it. This will be probably what I would call a landmark study. It will probably be a 10-week initial endpoint in this study, and we would like to continue the patients on placebo long term. So it's a placebo-controlled 1 year study with the primary end point at 10 weeks. The hope would be that, basically, we can, not only observe it at 10 weeks, but also show the continuation of the effect. We'll probably be using 2 doses, 15 or 30 milligrams, and this would likely require at least 450 patients worldwide which means 150 patients per group. Again, we expect to submit the final data from the study that I've described to you, Study 14 with the protocols for this study to the FDA and EMAP in the next quarter. With that, we move on to Slide 30, and Stefan, it's back to you.

Thank you, Ravi. I think this is just in a nutshell. You know that we have a partner drug on the market. I already mentioned that it is -- was the first NCE in more than 10 years in the U.S. and Europe, globally licensed double-digit percentage royalties in the countries where someone commercializes itself and mid- to single-digit royalties where that is license. We are intending and discussing with our partners in bond to perform a study that would differentiate the drug further but I will spare you the details because today's focus is really on evenamide. And on the last slide, where you see our partners globally on XADAGO. That all said, I hand back to Sandra, and we are very much interested to hear your questions.

[Operator Instructions] The first question comes from Bob Pooler from ValuationLAB.

First of all, congratulations on the fascinating interim data. A few questions from my side. Actually, it's a repeat of what I asked in January to both of you, what for you is the most exciting result in the interim data that you just reported today?

I think for me, the -- first of all, it's the totality of the data, but if you were to ask me to focus on one single aspect, I would probably say the clinical global impression of severity change over time. That's not driven by a scale. That's done by psychiatrists within holistic in assessment of the patient. It takes into account everything. And what's fascinating is it's not symptom. It's focusing on the severity of the disease. Severity of the disease, when you assess, you look at the quality of care needed to maintain the patient. Obviously, it means that the severity of the disease has gone down. The level of care needed has come down, and that's a very good outcome for the patient, for the family and for society.

Yes. I may -- as my sense to it, I mean the way we have discussed these effects with the specialists, the answer we got is, look, this is not an immediate cure. What we see here is a drug that is very slowly, continuously, up to 1 year, it seems like repairing a deficiency, putting things in order again. And this, I find absolutely fascinating. Somebody mentioned the word healing and I'm far away from using that myself. But it seems like this long duration of the study, that was a very wise decision as such, obviously. But if that can be confirmed in that second pivotal study, this is going to be truly magic for the patients with schizophrenia. .

And then a follow-up. What are your expectations for the day 14 results during March? There, you'll have more patients on the higher 30-milligram BID dose.

Theoretically, Bob, we always expect to see a linear relationship between those and this one. Unfortunately, in schizophrenia, as you know, to this date, no single drug have had a linear relationship. If you look at risperidone, basically, the best dose is probably 4 to 6 milligrams, forget about the 8, 10, 14. If you look at olanzapine, the 10 is probably as well as 20. If you look at -- in the metoprolol, it looks like the lower dose was actually more effective than the higher dose, same thing for loratadine. So although I hope that we get a bigger effect at 30 milligram, I would be very happy for the plateau, because of -- in fact, 7.5 and 15, you could have the degree of benefit that we have seen, that would be actually a very good thing, because that means you need to give a lower amount of the drug. But having said that, I keep my options open and if 30 milligrams showed a bigger effect, I would be very, very happy to continue with that dose forward.

So there would be possibility for titration also? So just keeping the patient on, for that, like, product and maybe…

No.

No?

Yes, I don't think we would do titration because I think in the new studies, we are starting 30-milligram as a starting dose, so there is no need for titration, and this is very well tolerated. We are -- as I mentioned before, we even get 60 milligrams single dose and it was very well tolerated. So I don't think there's any need for titration. Whatever dose we would prescribe probably would be the starting dose. But of course, if patients were at 15-milligram and they felt that they could get better, they could mostly titrate up to 30.

Okay. So another question is what can possibly prevent you from starting the pivotal study 3 in TRS?

I'm getting a lot of issues such as, for instance, the -- one of the complexities in doing a study in treatment in schizophrenia is trying to define the nonresponse. We have learned a lot from looking at the Lundbeck study, which I consider to have been very well done. However, they did not meet the outcome, which came out. So I think unless we get the right kind of investigators, et cetera, with that. From the regulatory side, I think it will be -- I don't really expect anything because we've already had one line of discussion. But if we got some extraordinary requirements, that would delay us from starting. For instance, if somebody said, no, you must do placebo-controlled monotherapy trial, I think that will be very difficult for us to do at this stage. Then I would actually reconsider how to go about that one. But having said that, on the preclinical data, from the clinical pharmacology data, from the clinical data collected to see tolerability and safety and from the signal of efficacy that we have seen here clearly, I don't expect that to be the case.

Okay. And then just one final on when do you expect a partner for evenamide? And what kind of agreement are you seeking?

I think, Bob…

I'll leave that to Stefan.

Yes. Thank you, Ravi. So Bob, discussions are ongoing as you can imagine. We have a lot of foreign companies who are following us on evenamide. And obviously, the results that we have presented in June, but much more in January and today has triggered a lot of excitement here. So clearly, the intention is that we will partner anytime soon, but not necessarily globally, because there's a balance here between the best case for our shareholders that would certainly kind of intrigue us into keeping the U.S. rights, for example, or keeping the U.S. and the Japanese rights. But on the other side, we obviously need some interim validation now for our shareholders, and we would also not have an issue with getting financial support for the next study. So I think this year will show us if a partner comes up with the right terms and makes the right offer, which is the best for the patients and our shareholders. That is a decision that we will have taken before this year is over and before we have effectively started the pivotal TRS study, but we will start preparing it ASAP.

Okay. So do you envision maybe partnering to occur before you have the results of study 008A?

Yes. I think the worst thing we could do, Bob, is that we waste time to market. With those results that we are just presenting to you, we must start this pivotal study in TRS without any delay. Keep in mind, if this drug succeeds and will be approved, this is a blockbuster and any year that we should lose on the market is $1 billion, so time is of the essence.

Congratulations again.

Thank you.

The next question comes from Samir Devani from Rx Securities.

Congrats on the data. Good to see it consistent with what you have seen on the third of Jan. I guess just got 1 question really. Just on what sort of granularity you get in terms of the blinded data, Ravi. I was just wondering, do you get -- can you assess this by the centers that are coming back? And if you can, is there any differences in the data coming back from different centers?

Yes. So I think your question is twofold. One is probably related to the fact that is there a difference between different centers. Sure, there will be some. Again, we're at a stage of the final study report, I can't say that at the moment that we have the data. But there will always be some difference. Also remember one thing, assuming that a lot of this is probably kind of driven by the kind of patient everybody has, somebody could be having a patient with schizophrenia, treatment with schizophrenia who's had the disease for 30 years. And another person could be having it for 8 years. In schizophrenia, the gospel is that basically, even in treatment-resistant, the younger the patient, the shorter the duration of the disease, the better is the response, so from that point of view. Second could be from the type of ages. I think that's probably what you're getting at. Could there be an inherent bias? Absolutely, there could be inherent bias. But that is blinded, the dosage, so that's a good thing. But if there was a bias, I think it would have probably reflected in by the 6 weeks, why would there be a continuing benefit at 6 months, 1 year? And if I was biased, I think that's the best improvement by 6 weeks. I would not get a better improvement at 6 months and 1 year. So I don't expect that's the bigger issue. But yes, there's division on differences, the difference is from center to center.

Our next question comes from Soo Romanoff from Edison Group.

The presentation was very comprehensive. I really -- and I guess a lot of my questions have been answered. So I really only have one follow-up here. The interim data was a really nice surprise and evenamide results were very -- a very positive differentiation from what's currently available. If we look at -- for the full results in March, I think in context, it will be helpful to go over the next key milestones to look out for.

Thank you, Soo. And yes, here are the next milestones. You will recognize that today, just like January 3, we have not given you absolutely detailed numbers, but we just gave you indications, because we need to protect the absolute numbers for our presentation at the conferences. So if you want to see the 6 months results in full detail, they will be presented at the ECB in Paris, March 25 to 28. The 12 months result, those that we have disclosed today, but not giving the absolute numbers, the absolute concrete numbers will be presented at the SIRS from -- in May -- from May 11 to 15 in Toronto. But then, really, new results, additional milestones will be the 6 weeks results for all 161 patients. So including the high dose, and that is due in March of this year. And the full result for the 12 months, 161 patients, that is due within the next 12 months and somewhere in between, we will also have the 6 months' results. Then later this year, we will have the results from the first pivotal study 008A, we will start the next pivotal study in TRS, and we might -- or we'll sign a partnership. So I would say this is material and massive news flow for the rest of the year just on evenamide.

Next question comes from [ Robin Davidson ] with [ New Science Found ].

I have a couple of questions, really. I'm trying to understand the data in some detail. The first one was the extent to which the benefit could be ascribed possibly to nonresponders dropping out between 6 and 12 months. I know it could not be causing benefit, but some elements of that might carry if we assume that the patients who don't respond are likely to be the drop out. So that's kind of the first one. Would you have any comment on that?

Sure, sure absolutely. No, that's the first thing we considered. And that's why the analysis that we have done actually if you look at it, it'd be [ LOCS ], so -- which is not going to be -- I mean, the data won't be artificially biased in favor of responders. That will be the observed case analysis, which we have done that also. By the way, the observed case analysis are slightly better. Now the question was basically with people who are not responding drop out. There were -- the patients who discontinued between 6 weeks and 6 months or between 6 months and 1 year, none of them are a nonresponder. We only have 1 patient in the whole study who has been not a responder. This worsened by 1 point and he was in the -- preserved in the analysis, so that's not the reason. The attrition rate, if you look at it, definitely, they're very low. And the reasons for drop out are basically the desire not to continue coming for visits and no analysis that we have done till now as being able to identify patients who are nonresponders. Nonresponders here does not mean they are worsening. Nonresponder only means they did not meet a very high level of benefit that we've used to describe a responder. So normally, you would use a patient who have any improvement on the CGI as responder. We said no, we will only take patients who had at least 2 categories for improvement in severity. On the CGI of Change, for instance, we normally take any improvement of a responder. We said no, we'd take only very much and much improved. Same thing on the PANSS. You could do an analysis where you could say 5% of the patients -- 5% improvement is good response. He's not worsening at least. We are none of that. We've taken 20% improvement. So that would not be the case, actually.

Okay. The other one I have, which is -- it's sort of sending us to the opposite direction is that on the absolute scales of PANSS, CGIS and the -- otherwise, the Strauss-Carpenter Score a patient who has completely normalized can't improve any further anymore. So there's this sort of aftereffect that could occur in that direction as well. Can you -- I mean, am I not thinking correctly here because is that an aspect?

I think I would love that case where patients improved so much, they couldn't get so much. So radically, you're right. On the PANSS scale, the 30 items, 30 symptoms to be rated. Each symptom is rated on a scale of 1 to 7. 1 means basically normal. You can't get below normal. So actually, the way -- if I want to sort of flavor the data, what I should have done on is actually subtract 30 from the total score at baseline. This would make the magnitude of improvement even better. But we have, till now, not seen any patient who have gone down to a score of 30 or even down, down to the score 40, to be really honest about it. These are treatment-resistant patients. They will improve, but they will not improve to that day and to that level. If they did, I would be in line for the [ middle ] price.

Yes, of course. I think the other thing really, I was wondering if you can -- I'm trying to understand the hypothesis, but the sort of increased improvement over time if you're simply normalizing the glutamate signaling in the brain. I mean, does it -- these become sort of feature that they're so learned, they take many months of treatment to unlearn, if you like? Or is that a way of thinking?

Yes. And that's a very good question. And I wish I had a really good answer. I could talk for about one hour and still not give you the complete satisfaction. I think you're absolutely right. The glutamate normalization cannot be the basis for this effect that we are seeing. I think the glutamate normalization, I could only imagine sets off a process which continues. Probably, it's got something to do with long-term potentiation, something to do with improving neuronal connectivity, synaptic efficiency and maybe even some new kind of protein synthesis, because this almost sounds, like, a repair mechanism. This does not sound like an amino transmitter blockade. That's when you expect to see the results in 1 to 2 weeks. So the FDA analysis showed that, basically, all the improvement that it's going to repair is in between 3 to 4 weeks. And we are seeing improvement in 6 months. And we're seeing improvement in 1 year. That cannot be then a neurochemical blockade. That is some other process. I wish I had an answer for how that seems to be happening. Probably it's beyond the capability of Newron to be able to fit in the van. I think you need to get a major pharmaceutical company or a major university involved in that asset. But I think all of the things that you said are probably correct. There is some degree of synthesis or something, neuronal synaptic activity increasing to unlearn or actually, to restart normal processes and that is taking a long, long time.

The next question comes from Leonildo Delgado from Baader-Helvea.

Congrats for the exciting results. Only question on my side, how do you plan to mitigate for any potential placebo response in the Phase III study?

I'm sorry, say that -- so could you say that again, last part?

So how do you plan to mitigate for any potential -- do you see a risk of having a placebo response in the Phase III study?

For sure. I mean, there's no study in schizophrenia done which is without a placebo response. If you look at the Lundbeck studies in treatment-resistant schizophrenia and unexpectedly, they got a very high placebo response. Now a lot of the placebo response, we call placebo response probably has got to do with noncompliance. A lot of these patients don't really take the medication at 1 time or the medication they're supposed to have been taking before, they don't take it. And then the same, not responding, but they actually are good responders and that's what happens when they get placebo. They come to the major state and response. So what we're going to do is 2 different things. First, we take plasma levels to make sure the patient is taking the background medication and they're taking evenamide when they're in that randomized trial. That's one thing. The second thing we're going to do is to make sure they actually take their medication every day. And for that, we're going to use artificial intelligence, where the use of a cell phone device or something similar. The patient -- the cell phone -- the artificial intelligence device will be configured to the patient and to the medication the patient is taking. And a patient, when they swallow the medication, they will have a cell phone given to them, and they will keep it pointed at their mouth and keep it pointed there for about 2 minutes. And this -- the swallowing movement is looked at and this video is transmitted to the data monitoring segment. The data monitoring segment using artificial intelligence checks if the patient really swallowed the medication or it's there in his mouth still. And then if the patient has not taken it, that signal goes through to the caregiver, goes through to the principal investigator of the site to say the patient has not taken the medication.. We will be able to reduce some -- quite a lot of noncompliance there. But if you're asking me, can you absolutely eliminate placebo response? I don't think anybody can. We can mitigate it and reduce it to a certain extent.

The next question comes from Irene Gabarda from Angelini Pharma.

Thank you very much and congratulations for the meeting data. My question is more regarding about the treatment-resistant schizophrenia criteria. Could you consider also injectables as a treatment-resistant patient or only oral antipsychotics?

In this study, I think we had a few -- we had some patients with refill. But generally speaking, the majority of the patients were on oral.

Okay. And other question is regarding about the drive price of the medication. Do you think that this is a weakness for the [ patronage ] of the patients? Or do you think that the patients are taking the medication twice a day?

Yes, that's a very good question. Ordinarily, even if you have asked me this, from a vast experience with Schizophrenia, I would have said basically twice a day with [ ignorance ]. But without going into too much detail here today, this drug actually is not depending upon blockade of a receptor. So what is happening is here, we certainly need the Cmax to precipitate the action. So what we're doing is we're giving the drug a short half-life. And Cmax is very rapid. The rate of rise of Cmax is really critical for the onset of efficacy. And giving you twice a day, what it's meaning is that you don't have a continuous blockade of glutamate, which would not be a good thing. As you know, continuous blockade would cause a problem. So we are getting basically a twice daily peak to the glutamate-release inhibition and that seems to be the working mechanism. It's the same thing as what you see in the cholinergic system where you see that phasic inhibition is better than tonic inhibition.

Gentlemen, there are further no more questions from the phone.

Thank you so much. So we have come to the end of this call. Let me please remind you that this was just news point milestone #2 for this year, and there are at least 4 of 5 coming. So please stay tuned. Thank you very much for attending this call. Thanks for all the questions, and talk to you soon. Have a good day.

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