Newron Pharmaceutical Stock

Ladies and gentlemen, welcome to the Newron Update Call. I am Sandra, the Chorus Call operator. [Operator Instructions] The conference is being recorded. The conference must not be recorded for publication or broadcast. At this time, it is my pleasure to hand over to Stefan Weber, CEO. Please go ahead, sir.

Thank you, Sandra, and thank you to everyone joining us today. I'm on this call with Ravi Anand, our Chief Medical Officer, who right now is in Tokyo, Japan. We appreciate the opportunity to speak with you directly about evenamide and ENIGMA-TRS Phase III program.

We have received, as you read this morning, the FDA's written communication regarding the clinical hold at the U.S. study centers in the ENIGMA-TRS 2 Study. Our team is reviewing the agency's feedback. And today, I want to share where that work stands and update you on the ENIGMA-TRS program. Let me start with saying that Newron has extensive experience in sodium channel pharmacology, including the development of Xadago, an approved product with sodium channel blocking activity on the market in Europe for 11 years and 9 years in the United States.

We are right now mostly focused on developing evenamide for people living with treatment-resistant schizophrenia and poorly responding patients with schizophrenia. The therapeutic options remain extremely limited. We believe that evenamide's novel mechanism has the potential to offer a meaningful new approach to treatment.

Our commitment to the patients we serve means putting safety first. We value our continued engagement with the FDA, and we appreciate the agency's focus on patient safety. Our 2 Phase III studies continue to make important progress with key milestones ahead for both ENIGMA-TRS 1 and ENIGMA-TRS 2. Let me start with the FDA's written feedback and what it means for the ENIGMA-TRS program. The FDA's concern relates to a possible association between sodium channel inhibitors and arrhythmias that may lead to sudden death.

In its written communication, the FDA identified a potential safety signal based on 4 deaths among patients treated with evenamide compared with 1 death among patients receiving placebo. And please remember when we speak about evenamide that always evenamide as add-on to an antipsychotic. And when we speak about placebo, that is always the antipsychotic alone.

These deaths occurred in 4 different studies in the year since 2023, 2 of them importantly long-term open-label extensions in which there is no or no longer placebo control. So it's important to note that the adjusted combined mortality of evenamide and the background antipsychotic was 1.31 per 100 patient-years compared to 1.81 per 100 patient-years for placebo, which in our studies always is background antipsychotic on its own.

Of the 4 deaths among patients receiving evenamide, 3 were considered unrelated to evenamide by the investigator. One was considered possibly related as 2 autopsies could not identify any compelling cause for mortality. The FDA also raised questions regarding evenamide's mechanism of action and the minimal shortening of the QTc interval observed on ECG.

The FDA notes that unlike QTc prolongation, QTc shortening has no established risk threshold or intervention threshold, and that a normal screening ECG does not reliably exclude latent sodium-channel disorders such as concealed Brugada syndrome, a very rare genetic condition with an estimated incidence of 1 to 2 per 100,000.

Newron has not observed the pattern of cardiac abnormalities or arrhythmias, neither in the preclinical or the clinical safety data generated with evenamide to date. The data includes findings from preclinical studies, a thorough QT study and more than 5,000 ECGs from over 700 patients with schizophrenia.

We believe the cardiac data generated to date provide an important foundation as we prepare our response to the FDA. Let me turn to how we are preparing that response. Our review extends across the full evenamide development program. The work includes a review of more than 10,000 ECGs generated across the evenamide program.

We are also reviewing relevant data from the broader schizophrenia field, including expected mortality in this patient population. Independent cardiac electrophysiologists are also providing input. Newron is evaluating additional cardiac screening and monitoring measures for ENIGMA-TRS 2.

We intend to incorporate those findings into our response and submit it to the FDA once that work is completed. So let me turn now to the progress of our ENIGMA-TRS Phase III program. ENIGMA-TRS 1 is nearing completion of enrollment with 497, I believe today, we should have crossed the 500 patients randomized to treatment and another 172 patients in screening.

We expect to reach that milestone of completion of randomization by mid-October. And top line 12-week data are expected in the first quarter of 2027. ENIGMA-TRS 2, the study that is impacted by the FDA hold on all the U.S. studies, continues to enroll outside the United States, 85 patients having entered screening so far and additional clinical sites are being added as planned and announced a few days ago.

We are encouraged by the progress across both studies, and we remain focused on preparing for the planned data readout. In closing my remarks, Newron priorities are clear. We are focused on completing our assessment of the FDA feedback, submitting our response and preparing for the planned ENIGMA-TRS data readouts.

Let's spend a second on the financial impact and sufficient funding requirements. We are funded through most of 2027, and that means from today's perspective, beyond the expected value inflection points, which are the 12- and 26-week results from ENIGMA-TRS 1 and the 12-week results from ENIGMA-TRS 2. And which are the key milestones investors should now monitor.

First of all, the completion of ENIGMA-TRS 1 enrollment as stated around mid-October, so in a very short time, followed by the submission of Newron complete response to the FDA and any FDA feedback or agreed protocol changes. The progress in non-U.S. ENIGMA-TRS 2 enrollment. The top line 12-week ENIGMA-TRS 1 data in Q1 '27 and updated ENIGMA-TRS 2 time lines when visibility are sufficient.

We remain committed to the responsible development of evenamide and most importantly, to the patients and families living with treatment-resistant schizophrenia. So thank you for joining us today and for your continued interest in Newron.

Sandra, we can now move to the Q&A session.

[Operator Instructions] The first question comes from Boobalan from ROTH.

Stefan, can you hear me okay?

Perfect, Boobalan. Good to hear you.

So maybe at a high level, I just wanted to start with sodium channel drugs because they have precedents for cardiac warnings and targeted monitoring, for instance, drugs like lacosamide. So I'm just curious whether in during your FDA discussions, there was mentioning of these drugs and can -- an approach that was taken for those drugs can be taken for evenamide as well? Or are they sort of signaling that they wanted to see the safety exposure package from the 12-week or 26-week package? I know it's a lot of questions bundled in one, but to the extent that you can answer, I'll appreciate it.

Boobalan, this is Ravi. Good to hear from you. So let me try to answer your questions one by one. The FDA has had concerns about sodium channel modulators for quite some time. You may probably note the report they wrote on lamotrigine. Sodium channel modulators can be both antiarrhythmic and proarrhythmic.

Safinamide -- I mean, evenamide is a pure sodium channel blocker. It has no tendency for a QTc prolongation. In animal studies, there is no evidence at all of any arrhythmias. This is despite studies done at the request of the FDA with 15 observations per day for 12 weeks, nothing happened.

24-hour EEG, 24-hour ECG, 24-hour video recording in freely moving rats did not indicate anything at all. We have about a tenfold safety ratio for the Nav1.5 receptor, which, as you know, is expressed in the heart. So there's always a concern, but we don't have a concern because it's a tenfold higher level of exposure needed. The FDA asked us to do a TQT study, which we did. And the evidence shows that basically the prolongation of QTc was actually shorter than with placebo. Then the FDA then asked us to do a special assay called the Vaughan Williams assay to look at the interaction of the type of sodium channels, and we did that.

And the results indicate that evenamide is a Class Ib antiarrhythmic, not an arrhythmic. Now the FDA's position is that these people died, and I'll go through the deaths in a minute. So there must be something, and they're focused on Brugada syndrome.

I can tell you that we have 100 investigators in the trial and not one of them has ever seen a patient with Brugada syndrome. And in Brugada syndrome, what happens is that basically, there is a QT shortening, which theoretically evenamide does do, but the extent of the shortening with evenamide is a few milliseconds.

It's not massive. It's not like 30 milliseconds, not 50 milliseconds. But the FDA's point is, well, we don't know what level of shortening is needed. None of these patients had any ECG abnormality. None of them had any complaints of like an extrasystole, palpitation, faintness, dizziness. No, they didn't have any of that, and they died. And the FDA -- this is the way the FDA is concerned is not so much that the drug did it, but because they couldn't find a reason, so they're saying it must be a usual drug.

Now among these deaths, for instance, we have a patient who died a couple of months ago. She basically tried to swallow 3 different pieces of bread at the same time and started choking. The daughter tried to resuscitate her, push the bread out of her mouth. She went blue and died.

Now do you think choking could be due to evenamide and this woman had already had the similar episode a few months before? There's another patient who died in his sleep, no abnormalities at all. Everything was perfectly okay. The FDA's contention was that maybe it was Brugada syndrome. And then the patient's mother informed us that the patient's father had died the same way many years ago.

At that time, there was no evenamide causing it. So it's not so much that there's a smoking gun that the drug has caused it. It's because the FDA can't find any reason and we can't find any other reason. So that's what it is. Two independent safety monitoring boards have looked at it, and they all conclude -- including cardiologists, and they all agree that there is nothing that they can say about it.

We have now asked electrophysiologists who are cardiologists to propose criteria that could weed out patients who are having Brugada syndrome or sodium channelopathy, which might also produce the same thing, and we will incorporate that input into the protocol.

There's no discussion from the FDA as to what monitoring. They themselves have said they don't know exactly what criteria to produce. So what they've done is they turned it over to us to say, you produce the criteria and submit it to us, and we will look at it. Now you mentioned some of the other things.

Now remember, most of the drugs that are there, they're not exactly, for instance, if you take quinine, it's also got potassium channel blocker. Then you've got drugs like procainamide, which make effect also. So this is not in the same category at all. Now one, we will be, of course, submitting the protocol to the FDA and discussing and trying to modify the population to exclude these theoretical patients with Brugada syndrome, which can only be done through a genetic test.

And as Stefan mentioned, you barely find any patient with it. But we will do the test just to make sure we satisfy the authorities that we have excluded those. I think that answers most of your questions, right?

Yes, absolutely. That's very, very helpful, very comprehensive. Let me just ask you a very hypothetical question just for our investors' understanding. Let's say the hold remains even after your 12-week and 26-week data comes out, let's just say. So how should investors think about evenamide's prospects in the U.S.? And also, is it possible for you to conduct TRS 2 ex-U.S. and bring TRS 1 and TRS data, assuming the data is positive back to the U.S. and then sort of file for an approval based off of ex-U.S. data? Just curious to hear your thoughts on that.

Well, I mean, it's not a hypothetical question. It's a real question. In the case of safinamide, the pivotal studies were done ex-U.S. We had no pivotal study in the U.S. We have studies done ex-U.S. and we filed in the U.S. to get approval. Of course, that was some years ago. So now things have changed.

First of all, if the 023 study, the ENIGMA-TRS 1 study is significant, showing significant efficacy and the 26-week endpoint is showing significant efficacy. That is a major, major finding. The first time ever that an add-on treatment improved patients with treatment-resistant schizophrenia. Secondly, the improvement was such that it also was there long term. I don't think the FDA has inherently something against good drugs. So I think if we were to submit that data to the FDA, I'm sure they would raise some eyebrows or they would ask some questions, but I would think definitely they would be open to it.

And if at the same time, we had a second study, the TRS 2 study positive. I doubt very much that anybody would say, no, no, no, you cannot do this out here. Don't forget the FDA has approved drugs without a single patient being treated in the U.S. You may remember the amyotrophic lateral sclerosis drug from Japan, where basically there was not even an IND in the U.S. and the FDA asked them to file an NDA. So I definitely think we would get an approval based upon that.

The next question comes from Bob Pooler from valuationLAB.

A few questions from my side. Unfortunately, the line is a little bit bad, so I didn't hear all the answers from the previous questions. But what specifically does the FDA need to see before lifting the clinical hold? Have they given any guidelines there?

Yes. I mean the FDA has basically said, we are not able to identify what criteria to put in. You work on the protocol, you put in some more safety criteria, you exclude patients who could be at risk. So what we have done is now we've finally given in and said, okay, if that's what you want, we will do a test for patients with Brugada syndrome.

Like I said to you, it's like maybe 2 patients in 100,000 or so.

Yes.

So we're wasting money, but we'll do it. We'll do a test for channelopathies, sodium channelopathies. I can't exclude them. Third, we will exclude patients with a very short QT, like 360 milliseconds, which I have to say that I have not seen a single one until now. We will exclude patients who during this -- any period in the study who show a reduction in QT, we will exclude those patients.

We will do more frequent assessments for things like are you -- I mean, how do you feel the palpitations, do you feel an extrasystole, things of this type kind of thing. So that's what we are doing. Then we will also modify the patient population to make sure that we take patients who are definitely not improving on anything at all.

So we're trying to make a much better case for risk benefit. And those are the changes which we are working on. Again, as you can imagine, this is such an obscure field and not necessarily a field for a psychiatrist to be in to find out things about Brugada syndrome. So we're going to have to go to outside experts, which we have done now, both in Europe and in the U.S. And probably in the next 10 to 12 days, we will file an amendment.

Okay. So yes, it seems you guys done a lot of work on this already, your thoughts there also with the independent experts. So what are the expected time lines for responding to the FDA and potentially resolving the hold? So that would be, would you say, 12 days or 6?

Let's say 2 weeks for us to file, and they will basically take 1 month to review.

And we are depending on third parties here. So let's make clear that these 2 weeks do depend on internal feedback from third parties.

Okay. And then yes, potentially then we could see maybe some U.S. sites coming on -- back on stream. Just in general, could you comment on your history with sodium channel blockers being put on hold by the FDA?

Yes. I mean we've had this experience safinamide.

I go way back with you guys, too.

That's right. Safinamide was put on hold for a very obscure reason. FDA thought that drug produced retinal degeneration. And this drug was partnered not just with Newron, but with Merck Serono, and the whole program was put on hold for more than a year or so.

Yes.

And then basically, they realized that, no, that was not the case. And that it basically, the hold was lifted. The studies were completed and we went on to get approval. And by the way, it's been very well tolerated and there's no issue at all.

Then with ralfinamide, the FDA raised the same concern that you've got seizures. This drug is going to produce seizures in patients, this that the other, reduce the dose, do this, do that. And we said, no, we think this is not a legitimate reason. We stick to this dose.

And again, went on hold. And we again did the analysis to show them the sodium channel blockers can produce seizures, but it depends upon what circumstances, what dose.

Under these circumstances for patients with neuropathic low back pain, there is no risk. And then after having spent 1, 1.5 years on that and doing a lot of work on EEG studies in monkeys, then FDA basically said, okay, go ahead. So it's not a new thing. I mean there are other sodium channel blockers, which have been stopped because of the potential risk.

So I think if you take a novel drug, when you ever take a novel drug, you're going to have novel issues to deal with. And I think that's what it is, that we are dealing with a completely new mechanism going into an area like treatment-resistant schizophrenia, add-on therapy, adding it on to other antipsychotics.

We're adding it on to clozapine, for instance. Clozapine, as you know, is associated with high mortality. So we are in a pretty -- in a quagmire. And that's why I think it's difficult to make any prediction of any type. But we have -- of the 500 something, we have 514 patients or so who have been randomized.

All are doing well. No issues with investigators, not at all.

Yes. Just how much do you believe the U.S. hold has slowed enrollment in TRS 2? And again, what was the percentage of planned TRS 2 patients coming from the U.S.

Yes, that's a good question. I had anticipated putting in 100 patients from the U.S. into the trial.

Okay. A quarter.

Yes, a quarter basically. So that was an agreement with the FDA. Of course, when this issue first hit, we slowed down the enrollment everywhere just to give enough time for the U.S. to be able to come back and put in the quarter. Now looking at it, I think we're taking a more pragmatic view. We will keep the U.S. sites open.

We will hope that we will be able to enroll patients, if not 100, maybe 60, maybe 80. And to compensate for that, I'm opening up additional sites in some of the countries. So overall time line should not be impacted by too much.

Yes. Because I think Stefan said in Q3, you expect then the top line results for TRS 2.

Yes. Exactly. So that's a 400-patient study. So we expect now that we will -- we are done with the ENIGMA-TRS 1, all the resources will go to ENIGMA-TRS 2. And it's already, I think, close to about 100 patients screened.

Yes. Just on the U.S. patients, typically, U.S. trials are a lot more expensive than non-U.S. trials. Is there maybe some upside of enrolling the non-U.S. patients into this in that respect that, yes, the delay costs you somewhat. But on the other hand, if you enroll and let's say, like a plan B, okay, if the hold continues, you just continue with patients outside and file those 2 trials because again, this trial has been FDA approved. What maybe your cost?

Yes. The TRS 2 trial is fully approved. It's ongoing, even the extension of the trial has been approved by some countries. You're absolutely right. The U.S. is far more expensive. At this stage, I will only say that basically, I will be ready to spend the money just to get this thing over with. But by expanding the study outside the U.S. and the U.S. number of patients going down, will probably equalize the cost difference.

Okay. And then just because it's very -- actually, we're in October, so Q1 is around the corner a little bit. Do you think that positive ENIGMA-TRS 1 data that materially can influence the FDA's risk benefit assessment because then you have basically the first Phase III trial results there if they're positive, of course.

That's true. However, if you remember, the design of the TRS 1 study is such that we will have the first results for the 3 months, but they won't be released, only after the 6 months data. And by the time the first 3 months results are available, 6 months data endpoint would have been reached.

So I don't think there's a major gain. I think it's probably better to go with longer data. And by that time, we will have the TRS 2 data we have. Of course, we will communicate the results of 3 months to the FDA in some way, but it won't be like in a formal submission saying, give us approval now.

Sorry, Bob and Ravi, if I can interfere here. We will have a press release on the 12 weeks results, which will confirm that on the 30-milligram dose, the drug, if it comes out positive, will have reached the endpoint and will have been safe and well tolerated. So there will be a communication on the 12 weeks results.

Okay. And if I may, just one question before going back in the queue. Of those 5 deaths, are there -- is there anything that's common like cardiovascular or whatever? You said that somebody died because he choked and...

Yes. One patient died because she choked on bread. Another patient who was on placebo died because he fell down from a window.

Yes. I think there's nothing else.

There is nothing like. There is no...

There's nothing like there's the common factor of cardiovascular in...

There's no cardiac symptom. There's no cardiac finding. And that's what is the difficulty. It's difficult to prove a negative. It's how to prove that it's not and there's no cardiac finding. And to remember this basically, I think Maryland University did a study of looking at deaths in schizophrenia and over 20% of the deaths in patients who have schizophrenia are sudden deaths. And majority are cardiovascular in nature, but no, there's no evidence of it. Even we find the evidence, we will not find the evidence now.

Yes. So there's no pattern. That's very important. I think that's why the other regulators say, okay, continue to go. And yes, again, if you have a Phase III trial and you treat for a continued period, just continuous people can die, of course, in [indiscernible].

Especially schizophrenia...

The next question comes from Joseph Hedden from Rx Securities.

Joseph Hedden from Rx Securities. Just one, I'd like to follow-up on what Ravi was saying about kind of managing with the FDA and introducing some amendments into the trial. And then going back to a line in the PR where we're saying standard screening ECG doesn't reliably exclude sodium channel disorders. So if you could just go through the kind of amendments to the inclusion criteria again. Is there something in there that can satisfy the FDA? Because this seems like a bit of a Catch-22 with this statement here.

I think the first thing is to try to identify the patients who could be Brugada syndrome or channelopathy patients. And for that, there's a test. Genetic test, it takes about 4 to 6 weeks to get it done. I think we are highly unlikely to find anything in that one, but we will do the test for every patient to say, okay, there's no patient with Brugada syndrome or sodium channelopathy in the population we have done.

Next, we're introducing a new criteria. One is patients with short QT syndrome, et cetera, would be excluded. Patients who have any family history of any cardiac arrhythmia would be excluded. Patients who have a short QT, meaning less than 360 milliseconds would be excluded. So these are the kind of things. Then also during the study, any patient who experiences QT shortening would be excluded.

Now other than this, there's not much more that we can do or consider at the moment, but we are open to the idea that we're thinking about things like maybe doing a subset of patients, do a holter. But we've already done holters before and the holters showed nothing at all. So that's basically what we are going in with these criteria and restricting the population slightly.

Okay. So talking about the genetic test for this very rare syndrome and 4 to 6 weeks to get the result, are you then having to wait 4 to 6 weeks to work out whether you can enroll the -- whether you can dose the patient? Or do you dose the patient first and continue if this?

Absolutely. First of all, we have a trial design, which has a 42-day screening period. So this is the first thing we would do for any patient who met screening criteria to make sure they get the result. We would never randomize a patient before getting back all the results.

We also have an independent eligibility committee. All the results go to them for every patient, and then they decide whether the patient can go in or not. So they would never approve randomizing a patient without getting the result.

The next question comes from Joris Zimmermann from Octavian.

Only a few minor ones from my end. Maybe on -- coming back to this assumption that the U.S. hold would indeed remain in place and then you file based on the other data. Do you have a rough estimate on patient splits per region? So how many patients do you expect coming from Europe, Asia, et cetera, by the end of the 2 trials?

And then secondly, also on all the amendments you just explained, Ravi, how do you think those would impact the label? I mean, would that mean that later on, if the data is positive, approval is granted, the physicians would need to run the test, for example, for Brugada syndrome or to prescribe evenamide to a patient?

Yes. Let me take the second question first. Many times during development, we do things which are completely bizarre, which if they were reflected in labeling, no patient would ever take. Let me give you an example. For instance, safinamide. We had to do retinal scans to put in patients with Parkinson's disease. And of course, once the drug is approved, that's finished. No need to do that anymore.

There are other compounds, for instance, [sertindole] basically where you had to do 24 special kind of ECG to look at people who would have vasovagal syndromes. Once the drug is on the market, you don't do that at all. So this would not be a criteria because this is only a theoretical risk, which the FDA has identified, there's 0 evidence that that's actually a real evidence this.

Regarding the distribution of patients, we probably have about 30%, 40% of the patients from Europe and maybe about 30%, 40% from Latin America and maybe 20%, 30% from Asia.

The next question comes from Helmut Fink from Verus Capital.

I've got 2 of them. The first one would be, I would be interested what really changed in between the beginning of July and now. You communicated that you had quite a positive constructive meeting with the FDA. And what you described now, what you are intending to do, it sounds like you're doing this now after you got the refusal of the lifting of the FDA hold. So the question is, what has changed now that -- yes, from the situation we have right now?

And the second one, the 4 cases, maybe you can describe that a little bit more specifically, which study that happened because I think there is quite a misunderstanding because I think some of them are cases that are not related to TRS 1 and TRS 2 studies, but to other studies as well. Maybe you can specify that as well.

Yes. Okay. We'll do. The first was a question of the FDA meeting. And I have to say there was a very positive meeting. Very friendly meeting, very good cooperation, discussion of the issues, et cetera, et cetera. And the FDA said, basically, look, okay, this is a good meeting, propose to us what you had to do, and that's what it is.

Beauty lies in the eyes of the beholder. We thought it was a great meeting. It was a great meeting. We reported it as such. And then basically, once the FDA went through the proposal that we had made, they didn't agree with it. And that's when the letter came back. And that's basically what we're doing. It's not that there's suddenly in between.

We suddenly found 20 ECG abnormalities, and that's made the FDA change. Nothing has changed since that time. There's no new submission of data. So that's basically what it was. It's just not that anything new happened. It's just that the FDA after having reviewed our protocols, felt, well, no, this is not going far enough. Maybe we need to do more. That's what it was.

Regarding the deaths, the first death occurred in an open-label study, which was 014/15 study in a patient who had 6 months of treatment approximately basically was fine, no ECG abnormalities, nothing at all was improving and then basically died.

Nothing could be found as a cause for death. There were some changes in the heart in terms of cholesterol deposits here and there, but nothing to say that this is really a compelling cause of death. So the investigator when pushed again and again by the authorities. He had originally said this is not related, the autopsy reports came back and they couldn't find any other cause, they said, well, maybe it's possibly related.

All the other deaths are considered not related. One was a death in a patient on placebo, so we let's disregard that. Then there's a patient basically in the first month or so of treatment, no adverse events, no ECG abnormality, no vital sign changes, no blood pressure changes, nothing of this type, except a remote history of cardiac disease.

Basically, the patient died in sleep. And again, no cause. Now most of these countries where the study, the deaths have occurred are Catholic and they refuse to do any autopsy. So that was ruled out. And then there's one more patient like that, a younger patient who basically died 39-year-old, died again in sleep, perfectly okay.

Otherwise, everything was fine. And then the mother of the patient basically came and told us that basically the father of the patient also died just like that many years ago. So obviously, at a time when there's no evenamide available. So probably it's a family genetic disorder, which was there. There was no evidence of Brugada syndrome, nothing at all.

Last patient who died was a patient who basically typical schizophrenia patient basically tried to eat 3 pieces of bread at the same time, got stuck in his throat, couldn't breathe, went black and blue, the daughter tried to resuscitate and push this out, could not do it and the patient died.

None of these cases sound to me like an arrhythmia. Arrhythmia just don't happen, the drop of a hat. You have extrasystole, you're feeling that you're not breathing well, you feel dizzy, you feel chest pain, something, nothing out here. So these are the deaths.

But 3 of them were -- you said the first one was at 015 and the other ones are ENIGMA 1 and 2...

There's no death in ENIGMA 2.

The next question comes from Wolfgang Lickl from APO Asset.

I hope you can hear me, I'm traveling. A question on the stance of the regulatory authorities from other regions like Europe, Latin America. Have those authorities seen all the data that the FDA has seen and have they explicitly that the study can go on? Or is there simply no communication with the other authorities?

The way things happen, I think under ICH rules, if there is what is we call as a SUSAR, which means sudden -- and sudden death, which is considered related, we have to immediately inform the health authorities. Otherwise, we basically inform the investigators of all the deaths. We don't even unblind unless it's considered related. So we don't necessarily unblind the data death occurs. It could only be once the FDA asked for it, what is the code, then we do that.

We basically received questions from the MHRA first, and we gave them the answers on what the reasons were for the FDA issues and no response after that. The German health authority contacted us on behalf of CHMP because Germany was the country which reviewed the protocols and they got a complete answer and complete documentation and after that, none.

Then the Indian health authority was informed of each and every thing because they are the ones who require every serious adverse event to be reported to them. So they looked at it. They took about 2, 3 months to approve the next protocol. But then after reviewing all the data, they approved it.

And lastly, I think it is an authority in Singapore basically asked for it, was submitted to them and there was no response. Health authorities never come back to tell you, no, no, no, you're perfectly okay to go ahead. But they will ask for something. If something is okay for them, then they will do not respond. If something is not okay, then, of course, they respond. So you will never get back a letter saying go ahead. So that's basically where we are at the moment.

Ladies and gentlemen, that was the last question. I would now like to turn the conference back over to Stefan Weber for any closing remarks.

Thank you, Sandra, and thank you all for participating. We had a very busy meeting today. We had excellent questions. I guess we could answer all your questions. I hope so at least. I would love to thank you for staying tuned to Newron. There is going to be exciting news in the months to come. And let's take this compound over the finish line in the next 6 to 12 months when it comes to our pivotal studies. As I said, stay tuned. Have a good evening. Bye.

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Ladies and gentlemen, welcome to the 2025 Results and 2026 Outlook Conference Call. I am Mathilde, the Chorus Call operator. [Operator Instructions] The conference is being recorded. [Operator Instructions] The conference must not be recorded for publication or broadcast. At this time, it's my pleasure to hand over to Stefan Weber, CEO. Please go ahead.

Thank you, Mathilde, and good afternoon, everybody in Europe. Good evening, everybody in Asia, and good morning and early 6:30, have a good starting to the day from Dana Point, California. As usual in the past years, we are spread over the world. The only person right now in our Milan offices is the CFO as he should be. He's sitting on the money that we need to spend in the upcoming period. Our Chief Medical Officer, Ravi Anand, is right now preparing for the SIRS, Schizophrenia International Research Society Conference that starts tomorrow. And I am attending the conference of ROTH Capital at Dana Point. So welcome to this call.

I hope you have had a chance to download the slide deck that we are going to guide you through, and I will start with Slide #4. So if we look back at the last 15 months and the period that we are reporting about, and I will then do the outlook for '26 and hand over to Ravi for the new science and R&D progress and then to Roberto for the financials and the AGM EGM that is upcoming. If we look back, this has really been a period that couldn't have been much better. We practically hit all the quick points. We made all the milestones. But what I want to tell you already now is that for the upcoming 12 to 15 months, we might see even better outcome. So be prepared for that. If we look back, and that is all about evenamide and schizophrenia for the moment. We have to start with the deal that we signed in December 2024, the validating deal with EA Pharma from the Eisai Group.

We did that deal with one of the top 10 Japanese pharma groups with a CNX experienced company, and there were some reasons. We wanted to validate our unique mechanism, the only drug that modulates glutamate in schizophrenia. We wanted to validate being the first add-on therapy in schizophrenia. We wanted to validate our claim that this is the drug that is the only one that qualifies to work in the vast majority of schizophrenia patients who are poor responders or treatment resistant to the current medication. We wanted to get an indication of the intrinsic value of that compound, which by analysts was after that deal was signed, estimated to be more than EUR 1.5 billion. And finally, we wanted to get the cash to perform our Phase III study because at that time, the markets were very challenging on equity. We got all that and since we signed the deal, and that is the starting point of the 2025 success story, we collected EUR 48 million, which was exactly the money we needed to advance our evenamide into the decisive pivotal study program called ENIGMA-TRS.

And as you know, that is split in 2 studies. One is ENIGMA-TRS 1, that is a 600 patients, 1-year double-blind placebo-controlled study, which was finally enrolling first patients in August after we had gotten the approval for the overall program in May. This study is right now actively enrolling on all target continents, and Ravi will give you more update on the status. Importantly, in December then, we could start ENIGMA-TRS 2, the second pivotal study. So 2 shots at target even if 1 sufficiently positive study should do to get this drug approved. We started ENIGMA-TRS 2 in the U.S. study centers with UCLA and since then have added Johns Hopkins and the other studies centers are ready to initiate, and we have submitted the documentation in all the other countries in which we want to enroll patients. So this study is up and rolling now. And again, Robbie will give you an update.

And then importantly, just by the beginning of this year, 2026, we could inform markets that also our partner, Eisai Group has initiated their Phase III program. So right now, I can say this is the most advanced clinical program in schizophrenia. We are right now running 3 pivotal studies in total with more than 1,300 patients in the world. And as you will hear later on, we expect results from the 12 weeks readout within this very year.

Now we did have absolutely thrilling. I'm moving to Slide 5. We did have absolutely thrilling 1-year results from a study in treatment-resistant schizophrenia when evenamide was added to best-selling antipsychotics. And we did have the first highly statistically significant efficacy results from Phase III study called 8A, but there was plenty of questions given the new mechanism and the new positioning. So it was very important that all the clinical results of the past have by now been peer reviewed and published in the papers. We have presented them at numerous conferences. All the space is now being educated about the benefits of this drug in those patients in which today's medications just don't do good. But it was very important last year in August that Pittsburgh University came up with a piece of research, which could explain for the first time why in the pivotal -- why in the Phase II and Phase III studies, we saw that ever increasing efficacy, doubling, tripling responder rates by 1 year, 50% patients no longer qualify as treatment resistant and for the first time ever, treatment-resistant patients being reported to be in remission for 6 months. We didn't know why and how our drug would do that.

And I think Pittsburgh has provided substantial explanation how this drug does so by qualifying schizophrenia as a disease that is substantially caused a hippocampus, a section of the brain where today's drugs simply don't hit, and that is why they do not improve negative symptoms, neuro cognition and why they only have limited benefits in symptoms. So that work of Pittsburgh now peer-reviewed and substantial support for the positioning of our compound and the explanation of the benefits we have shown. Again, starting this year, early 2026, we got another validation that is on a new composition of matter patent on crystalline forms of evenamide, which has the potential to extend our exclusivity to 2044. That would be 17 years post the expected approval of our compound, which we expect by end of '27. This patent has been submitted a year before, but ahead of time, the European Patent Office declared their decision to grant this patent in Europe in early January. The same patent is right now in the process of being reviewed, and we expect it to be approved also in all the other key territories, importantly, including the United States, where, again, this would give us exclusivity until 2044 and thus 17 years post the expected approval of this drug.

On the corporate ends, moving to Slide 6. All the excitement about our results and the initiation of the U.S. study triggered 3 U.S. analysts to start covering Newron and the fourth one joined from Europe. So we got plenty of new coverage. We saw doubling or tripling liquidity in the stock. We are right now trading between 0.7% and 1% of the stock every day, which is clearly showing us that we get better coverage around the world and more people looking at our stock. This is a process that must be continued and even further improved.

Very importantly, we also resolved 2 key issues on funding. Number one is that with existing shareholders and new shareholders from Europe and Asia, we signed a funding agreement in February this year, which will give us access to up to EUR 38 million, of which EUR 15 million are already in the bank, EUR 11 million will come before this year is over with no milestones attached and then the EUR 12 million remaining will come conditional to positive results of our pivotal studies by end of the year. That money being in the bank, we now have the funds to complete our ENIGMA-TRS 1 and 2 studies to the 12-point readout. So we will have all the money to report on the primary endpoint after 12 weeks and the secondary endpoint, and we will be able to advance our drug into NDA submission, and we will have a number of months of reserves beyond that point in time.

And the second component of improving our financial situation was that we reached agreement with the European Investment Bank that all future payments under our loan agreement would be delayed at least by 2 years and a quarter to not before June 2028. So we are now in a very good financial situation. We have 3 pivotal studies rolling, and we have all the cash required to get to read out.

On the corporate end again, our Board of Directors is already 1 year that Chris Martin has become our new Chairman. And I have to say that it is a marvelous cooperation between management and Chris, very much appreciated. He succeeded Ulrich Kostlin who was our Chairman for the 12 years before. In order to now complete the new setup of our Board of Directors and have completely independent directors on the Board, both Patrick Langlois after 18 years of service on the Board and Luca Benatti, after 12 years of service on the Board. Luca was the last founder of the company, have declared they will not stand for reelection in this year's shareholders' meeting. And I think we can say that we have found 2 outstanding new candidates for the Board, George Garibaldi, who is a highly respected industry [indiscernible] with years of experience and Paolo Zocchi, senior ex-partner in the top 4 audit company who are proposed for election by our shareholders as independent nonexecutive directors in the upcoming shareholders' meeting.

So what should we expect for this year, 2026 and early 2027? And I'm moving to Slide #7. I think it is worth to start from the end. If you look at where we want to be in the end and you remind yourself what are our peers. And the peers, the latest companies with one product nature in schizophrenia were Karuna and Intra-Cellular. And Karuna was acquired once they had submitted the NDA for their 1 product company -- for their 1 product to the FDA. They were acquired for $14 billion by Bristol-Myers and Intra-Cellular were acquired after they had launched their own compound in the United States, commercialized it for a few years up to $680 million sales with a market cap of $9 billion. They were then acquired by J&J for $15 billion. We are now the most advanced follow-up to those companies. So what are we missing? Well, to be fair, we are missing positive results from our Phase III program, and we will be getting to those results in the next 12 months. Then what they had, what we do not have, they were listed on NASDAQ. And that is something we cannot ignore because as we have lately seen again, about 2/3 of the global biotech money is traded in the United States.

So clearly, if you want to have full access to capital markets and you want to get a fair price, you should also have your shares listed on that largest stock exchange. So what we need to do is we need to work the path towards the results of our pivotal program. We need to prepare our NDA dossier. The initiation of the work must start way ahead of the results. Then something which is important that evenamide does not only work in schizophrenia, but like all the other compounds like Intra-Cellular's drug that has gone big in bipolar. This drug will also work in additional indications, and I'm also thinking of the elderly patients with dementia and psychotic episodes. This should be a perfect drug for those patients. And that is where additional indications should be pursued and Newron should start working on those.

Clearly, on the corporate side, we should strengthen our institutional shareholder base, and we are working with a number of supporting agencies to do that. And now this all takes us to the shareholders' meeting of April 2023 of this year because there is things that we can do on our own with the means we have and the tools we have and there's steps where we need the support by our shareholders, and we need to get the tools from our shareholders. And you have probably seen the agenda of the shareholders' meeting. There's the usual household stuff like approval of financials, then there's the important elections of the Board. And then you will see that we have also put on the agenda of the shareholders' meeting a capital increase authorization for 15% of the capital.

I do believe this is a moderate request, and it's clearly a compromise between aggressive strategy and the wish of some shareholders not to see any dilution. Clearly, the intention is that those shares would be used to advance evenamide in indications beyond schizophrenia and to support us towards submitting the NDA dossier and getting our drug approved. Clearly, also those shares might be used for a listing of our shares on a U.S. stock exchange like NASDAQ. And these are all procedures that need months and months of preparations. So what we are asking our shareholders for right now is not to approve a capital increase that will be put in place tomorrow, but what we ask them for is to give us the tools and the instruments that we need to start preparations and execute transactions at the right time, which also clearly means at the right share price to the right parties. So if the question is, is an IPO and uplisting of Newron stock to NASDAQ an option today, the answer is probably not because we are missing key ingredients, including share price results and other components. What we ask our shareholders for is support, providing us the tools and allowing us to initiate the process.

So your question might well be, so is it worth? What is the opportunity, and that takes us to Slide #9. What we have to offer today is truly the opportunity to transform schizophrenia treatment with evenamide. This is the first compound that offers glutamate modulation in schizophrenia, and we start understanding how much more important it is to go beyond the dopaminergic pathway drugs that have dominated schizophrenia in the last 70 years. This is a huge market opportunity. We talk about 1% of the global population, but the vast majority of patients is not well treated by today's medication. The vast majority of patients is poorly responding or treatment resistant. So what it needs is a completely new mechanism of action, that is what we offer. And what we need is the first ever add-on treatment to be approved in schizophrenia. What we need is the option for doctors not to change the current medication, but to add a drug with no additional side effects of relevance, but with additional incremental benefit. No risk of relapses, reduced risk of hospitalization, suicidality. That is the promise of such a new mechanistic drug, an add-on to the current medications. As evenamide is the first and so far only drug that qualifies as an add-on to any antipsychotic of relevance, including importantly, including clozapine, and Roberto will talk to that.

What we offer is highly exciting 1-year Phase II results of evenamide as an add-on to antipsychotics as well as highly statistically significant first Phase III results in a 4-week study in poorly responding patients. What we have seen is excellent tolerability, the most prevalent side effect being nasal pharyngitis in the Phase III study. I have already spoken about the potential of evenamide beyond schizophrenia that must clearly be evaluated. And we have also covered the topic of the strong IP protection. Right now, we have a Composition of Matter in the U.S. of 2035 and Process Patents to 2042 -- this new Composition of Matter 2044, that would be 17 years of a truly innovative treatment in schizophrenia, protection and market exclusivity post approval.

That all said, it's my pleasure to hand over to Ravi on Slide 10 for the update on science and clinical.

Thank you, Stefan, and good morning and good afternoon to everybody else. So I think I'm going to start with Slide 10, and I think this is a schematic presentation of how we currently view schizophrenia. And this has been brought out by the University of Pittsburgh and some of the universities.

Contrary to common belief, the schizophrenia symptomatology does not begin in the basal ganglia, but in the hippocampus. The hippocampus controls the rate of abnormal firing from the dopamine receptors in the basal ganglia. When it's not working, there is hyperfiring from the dopamine receptors, and that leads to some of the symptoms of schizophrenia. What has also become very clear is that the hippocampal nuclei control negative symptoms, control cognition. So you need to have a drug working there. All current antipsychotics work at the level of the basal ganglia where you have the dopaminergic receptors. And therefore, they will never be able to reach the hippocampal nuclei, and that is one of the reasons why we don't see any benefits in negative symptoms or cognition with currently available drugs. Evenamide at the level of hippocampus, it has no activity at the basal ganglia at all. And the data that I'll show you will convince you based upon the work done by Pittsburgh University that it works on all these facets.

I'm moving now to the next slide, Slide #11. So this is the experiment done. I'm very briefly describing this experiment. You should really take the effort to read the paper, which is fully published and it's on the Newron website. In this experiment, what was done by Pittsburgh University Research is they take rats, they give them a DNA alkylating agent called MAM. MAM changes the brain structure, changes the cytoarchitecture. The progeny, which are born basically show many of the symptoms and signs of patients with schizophrenia. So it's a neurodevelopmental hypothesis model of schizophrenia. You see hyperactive firing from the hippocampal pyramidal neurons, and that is reduced in this -- that this model creates and then basically get reduced by evenamide. What we see is the ventral pigmental area, dopamine neuron population activity is hyper and again, that is normalized by evenamide. Some of the most important findings are that the effects of evenamide outlast its presence in the brain and there's no way to explain it because the drug has a very short half-life, and this is way beyond that. This suggests that we are having the induction of long-term plasticity, which would be a very welcome thing for patients with schizophrenia.

And then as I said before, you will see data which suggests that basically evenamide improves cognition and improves negative symptoms in these animal models and likely, we'll be able to do that in patients. If I move to Slide 12. This is a wonderful experiment, a little difficult to understand, so you need to just concentrate on it. If you look at the first bucket, that's looking at the effects of neurons. We're looking at the active dopamine neurons per track and how they're firing. If you look at the first 2 bars, there's no difference because it's only normal animals, so there's no effect of evenamide.

The next 2 bars, you see the black bar, which is high up. That's because that's showing you increased abnormal firing in the MAM-treated animals. But the same MAM-treated animals, when they get evenamide, you can see there's a significant reduction. This is within 1 hour and the drug half-life is about 25 minutes. If you look at the second hour, there's no drug remaining. The drug has no active metabolite. There's no sequestration. But you see that the activity is actually increasing. The difference between the black bar and the blue bar is increasing. So even when the drug is not there, it's producing a benefit.

And if you look at the third hour where there's no chance even of getting the drug around, the effect of evenamide is going on increasing. It's reducing further and further the abnormal dopaminergic file. Nobody is able to explain this. We can't really fully explain this, except that this is a very welcome finding because what it suggests is that patients will continue to benefit from this drug for long periods of time.

Moving on to Slide 13. Now negative symptoms are present in all patients with schizophrenia. Even when patients improve from positive symptoms, negative symptoms don't improve. And one of the main reasons why patient functioning does not improve is because of the presence of negative symptoms. Now in this model what you're seeing out here, we have a rat in the middle. The rat has a choice to go to a toy chamber where there's a toy or to a social chamber where there's a real rat. Rats are very inquisitive animals. They love to interact with each other. So therefore, what will happen?

Next slide, if you see now what is in the next slide is happening is, we are looking at the MAM-treated animals. There, there is no difference between the toy chamber rat, the time spent sniffing or the real one. But if you look at the second -- the third and fourth bar, you can see the MAM-treated animals are not able to distinguish between the toy, whereas the evenamide-treated animals recognize, which is a real rat and they're spending a significantly more time on that. And this is not because there's any effect on locomotion, which is shown by the other graphs, but because the animal now which is socialized. Any socialization is a prominent feature in patients with schizophrenia. And this suggests that this drug will improve social interaction.

If I now move to the next slide. This is now looking at novel object recognition. This is a test of cognition. We take the rat, we give it an object. It familiarize it cells by sniffing. We then take it away, 1 hour later, we introduced the old object and the new object. The rat which is inquisitive, will memorize that, oh, this is the old object. I'm not interested. I want to go to the new object. Does this really happen? In the non-treated animals who have lost a lot of the neural architecture, there is no difference between the vehicle and the evenamide-treated animals -- in the evenamide treated because there's no deficit. But if you look at the non-treated animals, cognitively, these animals are impaired. The amount of time they spent on the wrong model, which is the Toy, the old object has gone down.

Evenamide is able to protect against that, and there's a significant improvement. So you're seeing an improvement in negative symptoms, you're seeing an improvement in cognition. We've already seen an improvement in firing rates. All this leads us to the clinical data, which is shown in the next slide. And then basically, I will walk you through that. So what have we seen until now? This is Slide 18. Evenamide has shown efficacy in virtually every study performed, whether it be a 4-week study, in early patients, a 4-week study in patients who are inadequate responders and a 1-year study in patients with treatment-resistant schizophrenia. In all these studies, it was given as an add-on treatment. The benefits of our ranging, they are seen on positive symptoms, they are seen on negative symptoms. The drug is very well tolerated. The attrition rate is less than 5%. The most common adverse event is nasopharyngitis, which means missing and the same incidence as placebo. What we've seen in the first Phase III study that we did in patients with inadequate response more or less confirm the results that we saw in the open-label study in treatment-resistant schizophrenia. It's one of the very few first times that I've ever seen that I -- all efficacy endpoints came out significant in the Phase III study, which is the 8A study, and this is published also.

All the endpoints reach statistical significance. And basically, what we are seeing is the side effect profile is so benign that you cannot tell the difference. Now we are basically looking at this, these results and the animal results because we are doing a 1-year study, where you expect to see efficacy continuing to improve over 1 year. Just to remind everybody, in schizophrenia, we generally have improvements in 3 weeks, 4 weeks, but rarely after that. That's why the FDA advises the sponsors nowadays to limit the study to 4 weeks because after that, there's no real improvement.

I move on to Slide 19 to show you the study 8A, which I talked about, the potentially pivotal study, which has now been published everywhere. It's a 4-week study done in 11 countries, 291 patients were patients who are on second-generation antipsychotic, received either 30-milligram bid of evenamide or placebo. All second-generation antipsychotics were allowed in this study, and the patients had to be psychotic.

The design is shown on the next slide. What we did in this study is at the very beginning of the study, we took blood samples to make sure that patients were really poor responders and noncompliant patients. We had the blood samples analyzed to make sure the concentration of the antipsychotic was at the right level to be able to ensure that they were getting a therapeutic dose. 30% of the patients had no measurable plasma levels, which tells us that they were noncompliant rather than inadequate responders. This study took us much longer to do because of this of the difficulty of finding patients who are compliant with medication. Ultimately, we got 291 patients. And as you can see, the study went up to 4 weeks, which was the endpoint of the study. The drugs that were allowed in the study, the second-generation antipsychotics are listed at the bottom, and they constitute about 90% of all second-generation antipsychotics in the market.

Slide 21 shows you the side effect profile of the drug. If you just look at the bottom part of the table where you see preferred term, the most common adverse event is nasopharyngitis. The incidence is almost the same as placebo. Again, then headache, which seems to be more -- almost the same as in placebo. What is more important is what you do not see [indiscernible]. You do not see any extrapyramidal symptoms. You don't see tremor, you don't see rigidity, you don't see akathisia. You don't see weight gain, you don't see diabetes. You don't see sexual dysfunction, no abnormal changes in the ECG or in the liver function test or kidney function test. No blood pressure changes at all. No severe sedation, no severe excitation. So it's a remarkably silent drug, which is ideal as an add-on treatment.

If we now go to the next slide, Slide 22. This gives you the primary results for the study. In line with the expectations from FDA and from ICH requirements that the primary measure should be the PANSS total score. So we designated the PANSS as the primary estimate for the study. The analysis are done in the ITT population. And as you can see from the fourth row, the null hypothesis, meaning there's no difference between drug and placebo is rejected with a p-value of 0.006. And the core secondary measure, which is the CGI of severity, meaning clinical global impression of severity is also significantly reduced with a p-value of 0.037. But that's not all. If you look at the next slide, this is showing you now the slope of the curve over a 4-week period of time. Obviously, this is not long enough. But you can imagine that if this study were to go on longer, the placebo group will keep on flattening, the drug group keeps on improving. And based upon this, we have designed the next studies.

This is the next slide is showing you the simulation in which we are imagining what would happen at week 12 and what would happen at week 26 and 24. What you can see is based upon the data from the previous studies, it seems like at week 12, we would have about a 10 to 14 point difference -- a 12- to 14-point difference from baseline, that is likely to be highly significant. Similarly, if you go to 26 weeks, we expect that basically we'll have a difference between 14 and 19 points compared to baseline, and that's likely to be highly significant.

Now I'm showing you some very interesting data. These have been published again. We looked at what happens to other antipsychotics when evenamide is added. Firstly, to our surprise, the clozapine patients, clozapine is the most effective antipsychotic. And even those patients when they get evenamide improved by about another 3 points compared to clozapine alone. But more surprising than that is olanzapine. Olanzapine is probably one of the most effective antipsychotic, has never come out second to any antipsychotic in the trial. And those patients, when they receive evenamide, they improve by about 5 points more than they get olanzapine alone. And this difference is statistically significant.

Overall, it looks like whenever you get patients receiving evenamide on top of a second-generation antipsychotic, they improve. And this leads us to believe that this could be a drug which could help all patients who are not doing well on their current medication. But what are the other results like in this study? So you can look at this, Slide 26, where basically we're showing you the PANSS responder analysis, clinically significant. In other words, 20% improvement, which is considered clinically significant in treatment-resistant patients with poor responders. You can see the effect is increasing over time and at day 29, which is significant. This rate, if it continues, you can imagine at week 12, we will have a very large difference between patients who are responders on current treatment as well as those who are current treatment and evenamide. But it's not only on the PANSS, we now look at the CGI of change. This is an analysis, which looks into account -- takes into account only those patients who show much improvement, not minimal improvement, only much improvement. And once again, by day 29, you can see almost a doubling of the number of patients who are responders on evenamide. Again, a very nice outcome. And if we continue this projection forward to week 12 and 26, we will have a very significant outcome.

Now I'm now going to just very briefly mention the pivotal ENIGMA trials which are currently ongoing. And I'm now on Slide 29. This is the TRS 1, the treatment of schizophrenia 1 study. This is a 52-week study. The first study ever done in treatment-resistant patients, which is placebo-controlled and 52 weeks. All patients have to be on treatment -- have to be diagnosed as treatment resistant. They are -- we confirm this by taking blood samples at the beginning, 3 times in 42 days to make sure that they are really taking their medication and even then they are not responding. Then the data are going to an independent eligibility committee, which really decides that these patients are actually treatment resistant. Then only the patients get randomized to 15 or 30 milligram of evenamide or placebo add-on. And the study is very tightly monitored, and we will look at the primary results at 12 weeks and the next results at 26 weeks and the last results at 52 weeks. And these results are the basis for which we will get the registration.

The 12-week endpoint is really necessary for showing the drug in an antipsychotic and will be the basis with which we file for regulatory approval, the first regulatory approval, both in CHMP in Europe as well as in the U.S.

The second TRS study is a shorter study. It's a 12-week study that is currently ongoing also, but that study has only got 400 patients into the 600 patients. And that study has just started. It's got approval in virtually all of the countries that we wanted to. And then basically, we expect that this study will also complete fairly quickly. We expect the TRS-1 study to complete enrollment by the end of August, which will provide us results by the end of the year and lead to hopefully to an NDA filing around the first to second quarter of next year. The TRS study will come in close behind that, so we will be able to include the results in that package.

With that, I turn it over -- we have done a lot of congresses this year, sorry. And you can see that on the Slide 32, we have a listing of all the congresses that we are presenting at. It's been a very busy season for us. Everybody is recognizing the value of evenamide and making up to a new mechanism of action. And all this paper, we have published a lot of papers, which you can also get from there.

With that, I turn it over to Roberto. And thank you for your attention.

Thank you, Ravi, and good morning and good afternoon to everybody else. So I'm on Slide 34. As you know, Newron is listed at SIX since December 2006. And since June 2019, we are also traded at Dusseldorf Stock Exchange, et cetera. By the end of the year 2025, we had 20 million -- around 20 million shares outstanding. Currently, they are EUR 20.8 million because of the capital increase Stefan was mentioning to you before.

And always at the end of December 2025, we have outstanding call option and derivative or warrants, if you prefer, of up to 1.6 million, of which 50% more or less were related to call options and the remaining 50% were the warrants that we granted to EIB. Let me welcome 3 new U.S. banks among our analysts, and I'm talking about Wainwright, ROTH Capital and Lucid, and they are on top of the already existing ones, so Baader, RX Securities, ValueLab, Edison and Octavian.

I'm now moving to Slide 35. Let's just talk about a few numbers. License income decreased. But of course, in 2024, we booked the downpayment of the Eisai deal. So no surprise here. And the value you can see are mainly related to the Myung In deal down payment and certain milestones that we got from the TRS 1 study progression. The other income, even if it's not a big amount, I want to talk about those because I'm referring the R&D tax credit benefit that we were able to book after 4 years of no additional benefit. And I'm talking about a couple of million, so EUR 1.9 million. What I want to tell you on top of this R&D tax credit is that accumulated, so since 2025, we got EUR 25 million of benefit. And so far, we have used EUR 22 million.

The financial results net decreased by about EUR 3 million. And the main reason is a technicality and IFRS technicality because according to IFRS, we are supposed to evaluate the warrant fair value and this value because of the increase in the share into increased by EUR 2.5 million. Please note that there is no cash impact related to this effect.

On the very last, I want to talk about the income taxes. Last year, for the very first time, we paid income taxes, while this year, the amount you see are only the withholding tax paid on the milestone and now payment received from the deals I was mentioning to you before. In Slide 36, so I'm showing you the balance sheet on the left and the cash flow on the right. So let me start from the balance sheet. What you see in the current asset in 2024 that is EUR 51 million is mainly the receivable related to the 8A Pharma deal that became cash. And this is why you see the increase in cash in 2025. While in the liabilities, the EIB loan last year was booked mainly in the noncurrent liabilities. And this year, you see everything in the current liabilities. But as Stefan was mentioning to you before, 1 week ago, we obtained from EIB the chance to delay the debt till end of -- sorry, till June 2028.

On the right, you can see mainly the bar on the working capital and the green -- it's green because it's generating cash and it's exactly the effect that I was mentioning to you before. So the cash in -- the cash we received in January and of the revenue that we booked in December 2024, partially compensated by decrease in brand and other payables.

If we move to the last slide. So on April 23, 2026, at 10 a.m. CET, we will have our general meeting. In the agenda, in the ordinary part of the agenda, the first point, as usual, is the approval of the financial statement. The second point is the approval of the new member of the Board of Directors. Stefan has already thanked both Patrick and Luca for being with us for so many years. And let me reiterate this concept because we really well appreciate their work and then I'm also willing to introduce to you, George Garibaldi and Paolo Zocchi as new nonexecutive directors.

On the extraordinary part, we will amend -- slightly amend, let me say, the bylaw in a few articles, and this is due because after 20 years and COVID, a few laws have changed and so we are willing to align the text of our bylaw to the new and amended shareholder laws. The second and the third point are a capital increase. On the second point, we are asking shareholders to grant 5% for option plans of capital increase. And in the third point of the agenda, we are asking for 15% of capital increase also potentially for an uplisting at NASDAQ and the point 4 is strictly related to point 4, 3 because the creation of ADR serves for the NASDAQ listing. Everything has been already uploaded or will be uploaded in our website. So if you want to look for additional information, please do not hesitate to visit the website. And with that, I think I'm done.

So I guess it is time for the Q&A session. I hand over to Mathilde from Chorus Call to introduce us to the questions by the parties who have registered for such.

[Operator Instructions] The first question comes from the line of Ram Selvaraju from H.C. Wainwright.

Congratulations again on a landmark year in 2025. You really are to be congratulated on how many fronts Newron advanced on. Firstly, I wanted to ask about your feelings regarding additional indications for evenamide beyond schizophrenia. In particular, we have seen evidence that other antipsychotic drugs, while perfectly serviceable in schizophrenia, actually turn out to be even better in other indications that are ancillary to schizophrenia that may constitute even larger markets. So I was wondering if you could perhaps comment on this. If there are other indications in which you believe evenamide is particularly well suited to have a therapeutic effect, what might these be, whether that would be bipolar disorder, patients with mixed depression and schizophrenia symptoms or others?

Thanks, Raju. You basically took my hands away from me. I would expect this drug to be highly effective in patients with bipolar disorder. Secondly, I think I would definitely like to go for treatment-resistant depression with psychotic features. And lastly, patients who have behavioral symptoms of dementia but cannot take second-generation antipsychotics. There, I think this drug, because it doesn't affect any neurotransmitter system will be very well tolerated and not have the increase in mortality that we see with all the other drugs.

That's very helpful. And I think we're all familiar with the intracellular therapies example that demonstrated just how large a market opportunity there could be for an antipsychotic with applicability beyond schizophrenia. Secondly, I wanted to ask about the information you presented regarding the ability of evenamide to augment the efficacy profiles of multiple second-generation antipsychotics. And if you could perhaps drill down on that a little bit further for us and give us a sense of whether there is a particular subclass of those second-generation antipsychotics that you consider evenamide to be particularly well suited to be combined with? And if so, what might be the kind of your top 1 or 2 choices? Obviously, you furnished a lot of information, in particular on clozapine, but I was wondering if you had additional granularity to provide.

Sure. I think clozapine because it's the most obvious candidate because when you talk about treating schizophrenia and clozapine, all the drugs, even though it's not used that much. Second, I think what has really been surprising for me and not just in 1 study, but in almost 2 to 3 studies has been the effect in combining it with olanzapine. And as you know, olanzapine and clozapine share certain features. So then the question comes up, really, is it basically because of the fact that both of these drugs are affecting D2 and D1. And -- but then what we see also is that is also affecting risperidone. It's also improving patients with aripiprazole. So I think this improvement facet is probably unrelated to the neurochemistry. It's a generalized effect on brain where it is acting in a way it's more like an antidepressant and produces some degree of configuration change in the brain receptors, which makes them amenable to treatment with the other drugs. I think we are monitoring this very carefully now in the Phase III study, and we're trying to collect plasma levels to exclude pharmacokinetic interaction as a reason for this.

With respect to the effect you showed of evenamide kind of having a long-term persistent impact even when the drug is no longer necessarily biologically circulating in the system. I was wondering if you could comment on, first of all, the long-term strategic plans at Newron to potentially explore the possibility of developing a long-acting injectable of evenamide. And if that is the case, how this information indicating long-term persistent effect of evenamide might dovetail with those efforts?

No, absolutely. I think as you probably know, some of the companies in Europe, which have been led the charge to develop formulation changes, especially in France and for TEVA, for instance, we are going to be in early discussion with them soon. I think to me, it's really a mystery almost that a drug which has only got a half-life of 25 minutes is affecting changes beyond 3 hours. But also in patients, we have a short half-life of 2.5 hours, but the effect seems to persist for more than 12 to 14 hours. So I think a long term, a depot formulation would have to be a very different type, but it would be a fantastic thing because a drug which is very well tolerated, doesn't produce EPS, doesn't produce sexual dysfunction could be ideal for giving long term, not only to the confirmed schizophrenia patients, but to those patients who are early on in their career, like the first episode patients or the at-risk patient population, that would be the way to go for those new formulations. And we would definitely explore that once we are done with the NDA.

And I think it's well documented that the long-acting injectable segment of the schizophrenia market is by far the fastest growing and at this point, probably the most lucrative. One last question from me. When do you expect U.S. office action on the COM patent that was already granted in Europe that would extend protection to 2044?

Stefan?

Yes. Ram, thank you for joining. Thanks for the questions. So we are right now in discussions with one of the leading U.S. IP consulting firms, and we are in discussion with the leading expert on crystalline form and solid formulations in the United States. We are discussing the strategy. As you know, there is 2 ways of getting a fast-track treatment of the Composition of Matter application in the United States. We are right now evaluating both. And I guess we will take a decision within the next few months. Depending on that decision, we might well see this patent being treated and decided upon before this year is over. And that means we might get that same patent application approved in the United States as per our expectation in this year still, which would be remarkable.

The next question comes from the line of Joris Zimmermann from Octavian.

Joris Zimmermann from Octavian here. Two from my side. The first one on your cash reach guidance throughout 2027. You mentioned that this includes EUR 50 million already received from the new financing plus another EUR 10 million that you expect later in the year. Question is on the remaining, I think, EUR 12 million from that new financing that is not reflected in this guidance. So that would provide you a further extension of the cash reach. And also in terms of the amended European Investment Bank repayment schedule, I would assume that this is already included in the guidance.

Okay. So let me start from EIB. Yes, EIB is absolutely included in the guidance, of course. As per the additional EUR 12 million, I am a very cautious CFO. So given that we are talking about something that is related to the data, I have kept this upside from these projections. So if data will be positive, most likely, we will see an additional injection of EUR 12 million. And this will, of course, increase the availability of cash in Newron most likely till the end of 2027. So this will give Newron additional, let's say, 6 to 9 months of time to strike the most appealing deal because of the positive data, yes.

One more question on the potential new indications and also a bit on the funding in that regard. You outlined the potential indications where you expect most benefit of evenamide. So in terms of your plans, how would that likely impact funding in the near to midterm? Is that already something in the plans? Or is that still to be decided upon?

I think it largely is still to be decided upon, but some initial activities are already included in the plans.

We now have a question from the line of Arron Aatkar from Edison Group.

Just two for me here. First of all, I just wanted to confirm that the ENIGMA-TRS 2 top line readout will also be in Q4 '26. I think I've seen some approaches where it's specified and others where it's not mentioned. And for this as well, would this come simultaneously with ENIGMA-TRS 1 if so, or will they be separate announcements?

Okay. Let me answer this. I think ENIGMA-TRS 1 is very, very, very, likely to be within this year. ENIGMA-TRS 2 is a borderline case, whether it's towards December or early January, things of this time. But both of them would be available to be included in the filing for regulatory approval. The announcements would definitely be separate.

Okay. Perfect. And my second question, I think you kind of covered it, but I was just looking at the licensing income of EUR 8.6 million. It sounds like that includes upfront payment from Myung In Pharma and also some milestone payments from both partners. Just wanted to clarify if you could provide like a breakdown on how much of the licensing income was upfront versus milestone payments from the 2 partners.

Yes. So the EUR 8.6 million are more or less 50-50, let's say, 30% related to Myung In and the remaining part related to additional milestone coming from EA Pharma. Sorry, I cannot be much more precise because I cannot disclose the final figures. But these are more or less the percentages.

Okay. That's very helpful. My other questions have sort of been covered off already. So no more from me. I just wanted to say congratulations again on the recent progress. Look forward to following the story.

The next question comes from the line of Joseph Hedden from Rx Securities.

Just wondered if you could say a little more on recruitment into the ENIGMA studies. Any information on how many patients today or progress in terms of are you on track with where you expect to be?

Yes. That's always a challenge. As you know, the regulatory process has become very prolonged nowadays especially the one in Europe, which takes forever and then the contracting progress though. So at present moment, I would say that 75% of the sites that we wanted to have initiated have already initiated. And we are basically just about coming up to where we should be. We have over 300 -- approximately 300 patients who have been enrolled in the program in the TRS 1. The TRS 2, as I said, has just got approval. So it's a little bit behind. But I think keeping the progress of TRS 1 in mind, I think we're very, very confident that we should be able to complete the enrollment on time for TRS 1 and then subsequently, the effort for TRS 2. The TRS 2 is a shorter study. It's only a 12-week study, and it's a smaller number of patients, only 400 patients compared to the 600 plus for TRS 1. So we should be okay with the enrollment time lines.

Okay. And then on the BD side, just wondering what you think the likelihood of any other regional deals ex U.S. for the ENIGMA results later this year, what's the likelihood do you think?

Thank you, Joseph, for the question. This will clearly depend if any interested parties will be willing to pay fairly and dearly for the new patent life that we have just added. And we understand that some parties might want to see the patent being granted first. But at the same time, clearly, with the European patent office decision to grant our patent, our expectations have increased. And as we have no cash urgency or lack at this point in time, we would be confident to go full steam ahead towards the results from both pivotal studies and then decide on how to deal with all those territories at the maximum value for our shareholders.

So that's the good news after getting all the funding done. We do not depend on income from licensing. But if there are fair offers, we will absolutely consider them. And yes, there could be other deals, but conditional to fair value, including the new patent life.

[Operator Instructions] Ladies and gentlemen, that was the last question. I would now like to turn the conference back over to Stefan Weber for any closing remarks.

Thank you, Mathilde. Thank you all for joining this call. I hope we have been able to explain to you why we believe this was an extraordinary 15 months in the past. But let me be clear, you please should stay tuned for the next 15 months because this could be much more exciting even than what we have seen in the last 15 months. This is really the opportunity to turn this company into a completely different size of company with a drug that might be approved and with a drug that we might decide ourselves to commercialize to get to the peak value for our shareholders and to secure the sustainable future of this company. So please stay tuned. We are happy to keep you updated. Looking forward to the next opportunity. Have a great day. Goodbye.

Thank you.

Goodbye.

Ladies and gentlemen, the conference is now over. Thank you for choosing Chorus Call, and thank you for participating in the conference. You may now disconnect your lines. Goodbye.