Erik Buntinx: Founder and CEO of ANeuroTech

Erik Buntinx, founder and CEO of ANeuroTech, shares his thoughts with BioBoss host John Simboli about leadership in biopharma and how ANeurotech is working to develop effective treatments, with minimal or no side-effects, for patients who suffer with depression

Transcript

John Simboli: 0:00

Today I'm speaking with Erik Buntinx, founding CEO of ANeuroTech, headquartered in Alken, Belgium. Welcome to BioBoss. Erik.

Erik Buntinx: 0:09

Many thanks, John, to give me the floor. We hope to have a very interesting conversation.

John Simboli: 0:13

What led to your role as founding CEO of ANeuroTech?

Erik Buntinx: 0:18

Well, John, I'm very happy with your question because this is a very personal story. So my role as founding CEO is something that came like. . . I was a clinician, already in my residence years in Leuven, Maastricht years, studying on depression. I detected some new mechanisms that could improve the antidepressant effect in treating patients. And based on that concept, I went to some very well known people such as Dr. Paul Janssen, founder of Janssen Pharmaceutica, to explain my idea and he was so enthusiastic that he allowed me to go into his library on all of these molecules that he synthesized. And I looked into that library, I see myself still sitting in that small room with all these papers, and all these booklets and looking for a compound that corresponds to that pharmacological idea and just found one. And that's the starting point of being a founding CEO. I found that compound, I could file a patent on it. And I founded, then, my first biotech company, where we developed that drug in relation to treating depression. I started with science, with clinical concepts. And went into the business, raising money. I've raised, up to date, more than 25 million euro. And my board was then asking me, Erik, what do you think about becoming a CEO? I said, I'm a scientist. similarly, This was really not realistic. I mean, coming from myself and confirmed by others. But just before I went into that role, I got pretty sick. And I said to these guys, at my board, look, this will not work because I have to undergo a very serious operation. And they say "No, no problem, Erik when you're ready other coming out of the clinic, you're welcome." And I went out of the clinic with still some tubes in me and I see myself at the first board meeting, where I was unconfirmed as CEO. So that's a little bit of my story on that.

John Simboli: 2:38

Do you recall, when you had your meeting with Dr. Janssen, that must have been dear to his heart, because your research apparently was very much something he'd been working on, something he was interested in. What did he think when you came in to talk to him?

Erik Buntinx: 2:53

You have to know I was introduced to him by a very good friend of mine, which was Dr. Paul Stoffels. He became afterwards head of R&D at Janssen. And this friend studied together with me, and he said,"Look, you have to talk with Paul." And I thought, I will explain to him the idea and then Paul can take that forward in his R&D environment. That was the idea. So I was very humbled to go to tell something, but Paul was listening. And he always has been somebody who is intrigued by "Where's the value? What is here to make a success?" And his reaction after my explanation was, "Oh, EriK, I will not do that. You have to do that. That's your drug. And you have to build a company on that." I never thought about that. But he said "You have to go back home. Talk with your wife, and tell the story." This was so convincing, that from that moment on there was only one objective and that's me building a company, becoming, also the founder and the CEO, And he has always supported me and that's respected.

John Simboli: 4:03

It sounds like as high a compliment, as one could pay to you to say this has merit, go build it. On the other hand, it was probably daunting to be confronted all of a sudden

with this idea: 4:14

Oh, I've got to do this.

Erik Buntinx: 4:16

Yes, indeed. And I was wondering why he replied like that to me. I learned from Paul, I discussed further with him. And he explained me to me that when you do this research work and also this business, what is absolutely key is that

John Simboli: 4:32

Let me ask you about the evolution from the person, the guy, who most believes it, he has to do it, because that belief will play down in the realization and the success. I think he thought, this we may not take away from him, from Erik, he's the inventor, he has seen this. He is a clinician, he knows the ins and outs, he has tried this already in his clinic. So he knows all about it. So that is the treasure that you have to explore. Because in biotech and developing drugs or treatments in patients, this is not only mathematics, it's not a kind of calculation. It's a dynamic process where you have to balance everything. And to appreciate what is important, what's not important. And that brings your product further. scientist to entrepreneur to building a company to trying to bring therapeutics to patients. So at what point did you realize that you had the entrepreneurial determination or energy to want to go out and suggest to someone, "Hey, I have an idea here?"

Erik Buntinx: 5:51

I must say this was appealing to own background, personal background. So already as a child, I was somebody who was very, very driven with, let's say, a kind of explorer attitude. And when I was eight, I think a teacher asked me,"What do you want to be in your life?" I said "An astronaut, of course, I want to explore space." And I want to go for these endeavors. And also, as an example, while I was 12, I was interested in astronomy, and then I went to my parents, who didn't know anything about science. They were farmers, in fact. And I say, I want to buy a telescope. They're really shocked. So Oh, my God, what is happening here? I was driven by science, but entrepreneurship, doing something, building something up. So always trying to realize things. So that is still in my blood, I think. And then you go for medicine studies, which is not really entrepreneurial oriented, of course, it's more about getting knowledge, know-how, training, clinical work, academic work, which I did. So I was then a little bit away from my entrepreneurial drive. However, it was always playing in my head, in my background. And that's also the reason why I have not become, finally, an academic. I was a research fellow at University of Maastricht, where I indeed discovered my hypothesis, and the foundations of ANeuroTech has been there. But that was pretty successful. I mean, that research work, and the professors proposed for me to become an academic, and to go for a chair. And it was yes, it's very attractive. I was in residence then,, but this was not aligned with my personality. And I had a very good friend, who was pretty much older, I think, 15 years older than me, he was, in fact, my insurance agent. I have good contact with him. He was also admiring what I was doing. And I asked him, What do you think about it? "Oh, no, it's very clear, he said, You never may be become an academic. You will be unhappy all your life." And I explained to him about my ideas, of course. And he said, "Yeah, that's your way." And really, I took that. I said, Look, that's clear. There is no reason why he would advise me, without reason. And so I went for my private endorsements, I founded my own outpatient clinic where big clinical research center was integrated. So we are currently doing very many clinical trials, sponsored. We are one of the biggest privately owned clinical research centers in Europe. And within that framework, I developed, further, my hypothesis. I discovered that work, with Janssen, I brought that into my research center, we did further research so that we could develop IP and so on. So you see, this is a very entrepreneurial background, mentality. And I think I got it from my parents. They were farmers and you know, a farmer is in fact, a real basic entrepreneur. You have to work on your field, on your animals, every day. Look what you can dok what you can do better. Otherwise, you will you will go down and this is a dynamic. I cannot miss.

John Simboli: 9:25

I never thought of it quite like that. There's no guarantee to being a farmer, right?

Erik Buntinx: 9:29

There's also another story on that because when I was around 14, my father also tried to do new things. I don't know how it wasn't in the U.S.,but here in Europe in this year, we are talking about 75-76, strawberries were coming up as delicacy. And my father thought, maybe we have to do that and I joined him and nobody did that. We built up a strawberry farming business that did very well. And I did that with him for four years.

John Simboli: 10:08

Yes, that's an entrepreneurial background. It's interesting. If we went back to where you were just a moment ago, and if your friend who's your insurance agent, were here and I said to him, "What was it about Erik's personality that made you know, right away, no, this is this is what I see." What would he say? What characteristics do you think he saw in you at that time?

Erik Buntinx: 10:35

That I'm always driven by my ideas, and that I'm a happy man when I can work on my ideas, that's for sure. And that I will be unhappy when I have to work on ideas from others.

John Simboli: 10:49

So you're having a conversation with Dr. Janssen, and, he said, in effect, it sounds like, this is an interesting idea, time for you to go home and talk with your wife and and break the bad news that you're going to start a new company. Do you remember what that was like? Was that an okay, part of your development and your growth? It's not an easy thing to do? I wouldn't think.

Erik Buntinx: 11:11

At first, I had the feeling I'm here in a fantasy, because you have to know I didn't have any experience in the form of business, at all. I didn't know really what a pharmaceutical company was. I didn't know anything about raising money, private equity, all of these things. And there is then the big Dr. Paul Janssen, who is absolutely a hero in the world, who is then saying, to me, and I didn't know him. That was the first time I met him. Erik, you have to go for your own pharma company. I came home, I'd said, Look, maybe this is something mad. What is this, an illusion?. So I had to digest it. Luckily, I was had a good friend, Paul Stoffels, who knows ins and outs, of course already then, and other persons we are still with me, all these guys said, yeah, you have to do it. And even better, we will join you, we will support you. So yes, really interesting. And so just you have to know the situation that I'm the CEO of a group, leading a group of people who have extremely in-depth experience as experts in this field. While I'm coming, in fact, from a kind of naive position. Step by step, I realized that then I was advised by my friends to go to an IP lawyer. I've never heard about an IP lawyer. I just went to the clerk, which is still my IP lawyer, and I said, "Look, I have to tell a story." And I told the story. And the first question, "I will ask you one question. Have you ever told anybody about this?" No. Only my friends." "Then we are okay, then we will follow the path". And yes,, for my personal environmental, my wife, etc. My wife has known me from when we were 17. So that's, I think, also very important. And already then, as I told, I was very entrepreneurial, I did things other kids didn't do. I owned my money, et cetera. So of course, it was a shock for her but it was also not surprising, at all.

John Simboli: 13:37

As I hear you tell the story I picture two words that are very similar but they're very different. So dream and dreamer. To have a dream, can be a creative act. And it helps people accomplish things they couldn't even imagine. To be a dreamer, we think of someone who may never accomplish those things. Maybe that's unfair to make it be that simplistic. But did you know you had a dream? Did you know you were not a dreamer?

Erik Buntinx: 14:05

Yes, the dream, of course, of being able to bring medicine to patients suffering from depression, and that's very personal because in my family from the mother's side, we had a lot of people suffering very heavily from depression, including suicide. So I was already focused on that. But then thinking that you could bring a treatment to all these suffering patients that you have discovered. Yes,, that's that's a legacy that give your life more worth I think, that's certainly, absolutely the dream. But no, I'm not a dreamer. I'm also not a romantic and I think that's the difference. I have a dream, or several dreams, let's say, but immediately I try to check. How can you realize that? What do you have to do in reality? How does the world work or the systems work to get something done? So, very focused on these kind of logistic business related concepts. And that's, I think, an opposite to a dreamer, because a dreamer doesn't want to do that reality check, because then the dream gets less attractive.

John Simboli: 15:18

When you were negotiating, or maybe that's not the right word, when you were working through that mixture of creative spark, and idea and realizing that the next step was to build something, you probably had a pretty good idea as a logical, rational, scientific mind, what it was that needed to be done to begin the process of building a company. But the CEOs I've spoken with many of them who are founders, also would have said to me on BioBoss, as a first-time CEO I didn't know what I didn't know, that sort of thing. So when you pictured what it would be like, in the very beginning, first few weeks, first few months of building a company, what was that picture? And then what was that reality? What was the difference or similarity?

Erik Buntinx: 16:05

Why, indeed, starting from this dream, and you think, yeah, once I can convince people to invest in it, and to join also the team, that they join your dream, and that they go on with that story. But, of course, people are people. And what you then see is that once they are there, and sitting at your board, for instance are in your team, then they are also popping up other things, which has nothing to do with your team, that has to do with politics, with their own profits, etc, etc. And, then you have to manage that. That is not always easy. It's sometimes also frustrating. So, why is that not so important for you, because we are working at something that is much, much bigger. And if you if you can be part of that, what do you want, more? If you get more options, less or more, I learned by the hard way that this is absolutely part of it. And you have to manage it. You have to take it with you for the better or the worse. And, that is important not to ignore, because everybody has to go in the same direction.. That I learned really, also, that's both for the managers, as you involve your collaborators, but also for your investors, which less often have the very personal views that you have to communicate with and to address to keep everybody in the same boat. Sometimes you have to manage some silly things.

John Simboli: 17:41

When you're setting out to first build a company, are there moments when you remind members of your team, this is my dream. I want you to be part of my dream, but it is my dream. Is that part of what's required to be a leader? Or can you share that dream? How do you do that?

Erik Buntinx: 17:57

That's absolutely required. Because if you're honest, if I'm honest with myself, I have also other choices to do other jobs also. To stay as enthusiastic and as convinced as much you will have to own your dream, and you may not let flaws in your dream, it may not undermine you your dream. And sometimes it happens, not by purpose, but it happens that there are ideas or ways that are presented that is not aligned with your dream. And if you allow that, then, at a certain value, you will realize this not why why I'm doing this, and that's a dissociation that can be very dangerous. So indeed, I must say, I must emphasize first very, very much that almost all people who will join me, they recognize this is the dream of Erik. This is his idea, and we join his idea and these people are so loyal that even more than I can say. But sometimes you have, here and there, also somebody of which do not expect that was not in that line and step by step is bringing his own interest, his own views and so a negative on your dream. And then you have to make a hard decision. Then you have to get rid of that person, absolutely. Otherwise, it will poison your own feeling, it will poison your whole team, your project. So I have learned. In the beginning I was very cautious about that. And if I think back I allowed too much, I was too soft. So in that respect, harder, yes. When I feel that there is somebody who cannot align with our strategy, with our dynamics, with our uncertainties, that is also part of the concepts. Then I say, look, we say better goodbye.

John Simboli: 19:58

Alright, let me shift to the more of a focus on ANeuroTech and how you're leading it. So is it possible to say in a very short and concise way, what the scientific idea is that you brought to start it up. What was the realization that you had?

Erik Buntinx: 20:17

Yes, so what we know in depression is that people are treated with antidepressants, that only half of them are responding well, the other half are responding somewhat. And then you have to ask yourself, what is the reason behind that? Why is somebody responding, let's say 99%, and another person 30%? And that brought me to pharmacology, how these things work. You have to realize, when I was research, resident in Maastricht, we only started to know how the brain was working in relattion to emotions and moods. And realized that receptors in the brain, so that are lending points 13 to 2a dopamine D4, very specific receptors in the brain, that if you could organize them at a relative level, that this could enhance, this could improve the effect of antidepressants. That was my thesis, a lot of research was done to show that this could be true. And then was the question, I said, can you find a molecule or synthesize a molecule? The answer on that last question was potentially impossible? So I got the idea, there, you see how the entrepreneurial drive is, maybe there is some compound and nobody knows that it exists. Then we did further research. And indeed, we showed that is true.

John Simboli: 21:48

Do you recall, where you poring through the literature, were you looking at data from previous studies? Do you remember a moment you said, this is the one?

Erik Buntinx: 21:58

Oh, yeah, that's, the so called Aha. Yeah, absolutely. I got that idea and it was expressed by certain scientific thresholds. So very specific numbers. So you take these numbers, and then you see what the profiling of these molecules are. And really, I went to a whole day to review all these papers and found nothing. And then I got that paper, and the strange thing is that Dr. Paul Janssen, together with Josee Leysen, who was at that time, his right hand in pharmacology, see is also a very big, big lady in this field, they just had published a paper with data from in vitro/in vivo, it was a combination. And if you look at these different compounds, and if you looked at this cross very carefully, then at a certain point, I saw oh Pipamperone is just different. It's just different from all these. While they had put it in a whole group, because it was the same chemical structure. They even, themselves, didn't realize that this was different. And that was the big aha. Then, oh, how can you then make these specific qualities of the drug clinically relevant? And I studied further, and then the idea was if you reduced those, extremely, that's not by 10, that's by 100, and even 200, and then maybe it will be so selective in the brain. And that was my invention. Nobody thought about it. Nobody had used it. And so that that was the invention.

John Simboli: 23:50

What that reminds me of is, I can't remember which founder or scientist who it was I spoke with, but he said, the aha moment is not sudden flash of light realization. It was a"That's funny", as he looked at the data. "That's funny, something doesn't quite add up here. " Was there an aspect of that was an illumination or was it? Let me think some more about? Somthing's not . . . I've got to look further here.,"

Erik Buntinx: 24:17

It was both. It was illumination, certainly, because I saw these figures. And when I saw it, at a certain moment, you see certain aspects that you've never seen. And then, once you've seen it, you continue to see it. But also the second point, is this really . .. can that be? Because nobody has seen this. This has been used in a complete other way. So let's check if that is something relevant, that can be true in a human brain. And so with that, I went to my IP lawyer, but I also went to a good friend who did imaging studies on dogs. I told him I said, yeah, maybe we could try to show that in a dog. And so we made a paradigm with that work. And we treated several dogs. And we saw, yeah, look, this is certain to 2A antagonism. And we see nothing else. And so the dogs, helped to realize this idea.

John Simboli: 25:27

That's remarkable. I can't pick another word. You've taken that idea, you've tested it out a bit, you've worked through the imaging with the dogs, you're ready to go, you're building this company, then you have to begin to tell that story, I would think. in a way that investors will grasp at the very beginning. So when you're bringing it down to that really essential part of it? And they say, Well, okay, I'm glad to be here today. Erik, tell me what is ANeuroTech, at that point? What is the answer to that?

Erik Buntinx: 25:57

Well, I think that's very specific for my situation that that ideas be founded on my scientific work. And secondly, also my clinical work, because we could use, already, this work in patients here in Belgium. And with these data, I really went to all these interested people to show look this is what I've seen as a clinician. You believe it or not? And yeah, that's also again, also personal. And you try to find signals, you adapt based on your findings, your concepts that is most feasible, most effective. And that's that's how we have done it.

John Simboli: 26:42

I think you've addressed this, why didn't anybody do this before part, but let me ask the question. So in those early stages, I'm guessing that there must have been some investors who said, this seems really interesting, Erik, but if it's such a good idea, why didn't anybody do it before? How did you get that question? How did you answer it?

Erik Buntinx: 27:01

I still get this question.. The explanation is, in fact, scientifically, because that's also a coincidence. Probably, but at the time that I was a research affiliate at Maastricht, the whole of the goal of monoaminergic theory of treating depression with all these neurotransmitters, such as serotonin, dopamine, was then very hot. I had luck, also to have a project be headed by my professor who was, at that moment, one of the absolutely key opinion leaders in the world on that monoaminergic pharmacological thesis. And that stimulated me, of course, to think about it. But how the knowledge about receptors in the brain, I'm telling you, talking about 1991 or 1992, was just emerging. And so that plays down, I developed concepts that were just busy with receptor OOG, selecting receptors from cells, and then see what are the affinity that works for receptors can be a little bit compared to what happened with the mRNA, that's also something that is new, and all of the sudden, it is reality. And so, let's say I was busy with that. Other people discovered things, I came to the idea. And this logic that before that, nobody came to that because the science was not there. Nobody knew anything about how receptors were working. We had no common knowledge, let's say. You have to realize that this is only more than 25-30 years, not earlier. Drugs were found by, on the one hand, chemical synthesis, and then you treated animals with that. And based on what you saw with animals, you say, Okay, this is a drug working for high blood pressure, but you didn't know how it worked.``

John Simboli: 29:12

I want to ask you more about the mechanism. But first, let's talk a little bit about the gap, the gap between the standard of care that you knew about when you first developed this idea, and then how it's evolved, and then how what you're trying to do, what you're working on, how that meets that that gap for patients?

Erik Buntinx: 29:31

Well, honestly, John, it's a sad story, but that's also the reason why we have to work very, very hard for that. The sad story is that, let's say, in the last 30-40 years, no real improvement in treating this devastating disease such as depression has been realized. There have been new molecules, there have been new techniques, but they are coming at pretty high safety cost. so that people have safety problems, adverse events, which frequently also continue and get worse the longer you take it. So that's not a very attractive treatment. Or they have a high safety burden, or they are very complicated, with a very high level threshold. So that's not accessible, too expensive, and certainly not in the long term. So a good solution for patients suffering from this disease, as chronic disease, namely, that you have an easy to take or easy to adapt treatment at almost no safety costs, not clinically relevant. It's simply not yet there. And with our a ANT-01, compound as adjunctive treatment, we think that we have that. The data are showing that you can treat patients adjunctively with our compounds, at in fact, no clinical relevant digital safety burden. And that once the patients will get their response, that response is very substantial. In that way we see that most of these responders are continuing to take this for years. In my sample, which I observe and treat, the mean intake is currently 11.1 years. So this is different from the current and still unsolved treatment problems in that in that space.

John Simboli: 31:29

What is the scope in terms of numbers of patients? And what is the severity? What are these patients lives like now, who have partial or incomplete answers?

Erik Buntinx: 31:41

Well, the main problem is the negative outcome that we translate in what we call treatment resistant depression, TRD. Everybody's talking about it. Well, you have to realize nobody starts with TRD. S omebody will get his first depression, it's not a TRD patient, he becomes a TRD patient, because all his treatments that he went through did not respond sufficiently. As with cancer, it's very hard to say that, if your treatment is not responding well, you will end up with your cancer and also dramatically with that. So that is what what is very important. We have to have developed treatments which prevent the risk to become a treatment resistant depression patient. And that is by having, as quick as possible, treatments implemented in the patient which will bring the patient to full recovery, brings the patient to a full resolution of all their symptoms, including what we call residual symptoms. A lot of patients who have depressive episodes do have residual symptoms, as they still have problems with, for instance, their level of feeling pleasure. So they feel not that pleasure feelings anymore than they had before the depression. They have also cognitive problems, they have not the concentration capabilities anymore that they had before. This is not a consequence of depression, which was often thought. No, it is unsolved residual symptoms. And these residual symptoms, as you can imagine, are of course, the basis, the seed, for the new episode. And so that's the reason why depressions are cycling. So you have to attack these problems very efficiently. And there, I think, we have something that, not for everybody, of course, that we don't say, but if you have a drug or treatment, whatever, again for you to resolve the whole palette of symptoms that you're recovered fullly, and you can continue that treatment because then it protects you from a relapse at no safety costs. You have no weight gain, you have no Parkinsonism you have no metabolic syndrome, you have no hypertension, and you continue that for your whole life and it protects you from a new episode. Well, this is fantastic. Then you prevent depression as a chronic disease.

John Simboli: 34:14

That sounds like the the word that we're all very careful about not using. That sounds like the word cure. Would you use that word?

Erik Buntinx: 34:23

Absolutely. I think we have to change the paradigm. As you can imagine, I'm a psychiatrist by training and people who know me from also my, my first years of residency, I've been called an atypical psychiatrist, very entrepreneurial, dynamic. I want to get problem solved. I'm not so big a fan of the care model, I must say. So we have to cure. For me, it's still shocking how much is invested. And that's okay, I can understand that. I'm not against it. But it's shocking that so much is invested in care, which has to be, but less in cure. No, we have to try to help these people with the cure. That has always driven me, also, in my own clinical practice to bring people back to their normal state.

John Simboli: 35:25

Is it possible to talk about what is clinical depression and how severely it affects the lives of people you're trying to treat?

Erik Buntinx: 35:33

I can, I think, start with a very simple comparison. When we awake, we have a hunger, we feel energy to get up to do things that are what we call vital elements. And your mood is also such a vital physiological phenomenon. So you wake up and you feel interest. You feel some interest in experiencing doing things, whatever. A person with clinical depression, has lost that vital mood experience. So when he awakes, he has not a feeling that something is interesting, that something can give them pleasure. That the whole day is one big, let's say, burden. They wake up and they think, Oh, how quickly will the evening come? And that's the key of depression. So in your brain, similarly, your mood center is just not clicking on, or it is clicking on a little bit, and then going away. And that is not going to put you on the level that you need to experience your existence as meaningful. And we, as conscious subjects, think that's the opposite with animals, and most do not have clinical depression, that as we are conscious subjects in our consciousness, we must have also that mood experience. So because you can say to yourself, when you wake, is this a day that I enjoy, or I hope to enjoy? Or is there the day that I do not want, you can make that. So normally your mood will say this is the day, a new day for me. But for a person with clinical depression, not the case For the therapies that you're working on now, what specific anymore. So they lose the fundamental feeling of meaningfulness, which brings hopelessness, which brings also suicidal ideas because what why am I here on this world? What am I doing? Maybe it would be better if I were not walking on this planet. And that holds together with other vital elements such as appetite, sleep pattern, concentration, all your system is then taken down. So your mood center is something, a core center that that drives also other vital functions. We know that has to deal with, of course, the brain. We know that certain regions are involved and certain pathways are involved. But we don't have any idea about the cause. The root cause is not known, although there have been executed massive studies on the relation between life factors, life events, and depression. Much of this big research has been able to make any relevant association between life events and depression. parts of depression are you hoping to address and how many of those folks are there? It sounds like depression is not a one time thing in someone's life, it may be multiple, How many and how often and what do you hope to achieve? The problem is the incidence. So the frequency of depression has grown enormously in the Western world, that at least we know. And pre-COVID, we were about 8%. And now post-COVID, we are at 12%. So that's enormous. And the big part of that is also within youngsters. Why that is, that's fairly difficult to explain, but it's very often. You may simply say that one in 10 persons are confronted with major depression at least once in their life but often repetitively. We see a lot of know also in the clinic, older people, people of let's say 65-70-75 which was thought rare 20 years ago, but these people want to have also a quality of life. But it also a very interesting observation for us is that if you have a medical history of these patients aligned and you see that their current depressive episode is not a single episode. Then they say, when I was 21, there was a period at 45. And now the third time. So there is a predisposition, often recurrent. And I said, before, the periods between one and the other episodes, mostly are not giving a full resolution. There's always some baseline of some depressed feelings here.

John Simboli: 40:27

That's very helpful. This is a bit of a jump, but let's talk about the mechanism of action. So how do your drug candidates work? What is the mechanism of action?

Erik Buntinx: 40:37

That fundamentally stays with what we call the monoaminergic hypothesis. That means we have a group of chemical entities that we call the monoamines. And these chemical entities are mainly in the brain playing between the neurons—serotonin, dopamine, noradrenalin, are very typical chemical entities, in fact. And you must see this as a kind of messenger. They are produced by the cells. And they are then transported from the one cell, one neuron to the other neuron, to give a message or messages. And so the brain is talking with itself. And that communication scheme is, in my opinion, disturbed in patients suffering from depression. And by having some influence on that talking system, by enhancing the serotonin, by reducing some receptors that are responding on these neurotransmitters. So you regulate a little bit, and that's little bit trial and error. But regulating the communication system can bring back the normal moods management. It's a little bit like, let's imagine that you have your cell phone, and some apps are not working, because there's a bug in it. There is something wrong with communication. And your IT guys says, reset. Well, it works. You say, how is that possible?

John Simboli: 42:05

Would it be accurate to say you're not trying to change the chemistry in the body? You're trying to bring it to its natural state?

Erik Buntinx: 42:14

Yeah, absolutely. You're not trying to change it, you're trying to improve their natural working. You're trying to bring back the normal communication strategies, so that they can do their job like they have done before. It's a restoration effect. And sometimes you must support that continuously to make sure that the system is working normally. That's something that I think we do as human beings, and even animals are doing that all day. I mean, you're wash yourself repeatedly not to get some bad things on your skin. So you're supporting your system, so that it can function well. And that's, I think, how you could adress depression. There are other therapies, of course. They are more what we call invasive, and are bringing in what we could say, not naturalistic effects, effects that you would normally not have. I don't think that that is a solution, I think that they can give an effect, that's a kind of induced effect. But it will be very surprising, if you do that, that you will get a sustained effect. If you do something which is not common in nature, mostly, it's not sustainable, I mean, then you can get counter-actions in nature. And these counter-actions will lead at the end of the day to a kind of neutralization of your induced effects.

John Simboli: 43:46

As you look at where the future of treatment for depression may go, and where your talents may alter how things are done now, how would you like to change the direction of where things are going?

Erik Buntinx: 43:59

I think we have to go together for being more ambitious in taking mental diseases very seriously, as an integral part of our human being. It's not a separate part, it's not a strange part, it's not a part that is for some people. In previous times, we put them in some Institutes. No, it's everywhere. So the focus of treating that and resolving that must be also everywhere. And then we go forward with with our human being. What has driven me always is, as you mentioned, is getting results. I want to realize something that is meaningful and that gives me meaning for my life. I have some some talents, I got them, they were given to me by nature, and I could not accept from myself that I would not use them and I would not try to do something meaningful with them. That's for me a very important issue. That's another question, I'm working very hard and now 61. I can stop working. And a lot of people say to me, why are you working so hard, Erik? You're old. I say this is my life. I cannot spoil my time for things at no meanin. That's really, really true.

John Simboli: 45:20

Erik, thanks for speaking with me today.

Erik Buntinx: 45:22

Thank you so much, John.