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Eduardo Bravo: CEO of Citryll · BioBoss

• 0:00
  John Simboli: as CEO of Citryll?
• 0:02
  Eduardo Bravo: Thank you, John.
• 0:02
  Eduardo Bravo: Thank you very much for inviting me.
• 0:04
  John Simboli: What led you to your role as CEO of Citryll?
• 0:08
  Eduardo Bravo: I did many years of Big Pharma, and then I had a very large job as the CEO of a biotech that started in Spain and then moved to Belgium. I moved to the dark side for a couple of years, where I was the operational partner of a SPAC out of of LSP, then EQT. And when we finished that, and we, you know, reverse merged into Oculus, which is a fantastic company now quoted in NASDAQ. I just, you know, had this conversation internally and said, like, you know, I have the energy to do another one. And what I missed over those two years in at EBAC was the day to day adrenaline, as I call it.
• 0:49
  Eduardo Bravo: And then, you know, started looking. Fairly quickly, you know, Citryll came to my attention through one of the board members, Daniela Couto, and I started exploring the company. Two years later, here am I.
• 1:03
  John Simboli: During the exploration. What were the factors that made that stand out related to all the other ones you were looking at?
• 1:09
  Eduardo Bravo: The disadvantage, hopefully, for this, an advantage, of not having a scientific background is that I was relying on, actually, the scientific due diligence having been done by other people. But you know, when you look at most of the companies that I was looking at, all were backed by very well known VCs. So you know, I don't think that there's anything that I was going to discover on my due diligence that had not been discovered by the VCs. If they were happy to invest and continue to fund the company, meant that at least they believe what they were doing. So for me, the scientific tick is done by third parties, if I may say so. Then for me, what made Citryll a very special case was, one, despite lack of scientific knowledge, the science was super easy to understand. It's almost, you know, pretty intuitive, provided you believe, in all the mechanisms that go afterwards.
• 2:10
  Eduardo Bravo: But, you know, the idea is a super simple idea, and it was very novel. I mean, it's first in class. No one has ever been able to target these NETs. And, you know, this can have such an influence on such a number of diseases, that I thought like, you know, I spent 13 years developing something that was super strange and rare for a very minor disease, and that gives another satisfaction. That product made it to the market.
• 2:40
  Eduardo Bravo: So we we did that. Now I was like, Wow, this drug can change the industry. That's how I see it. And I said, Well, this is the sort of, if I'm going to devote five years of my energy into something, I want it to be as meaningful as that.
• 2:54
  John Simboli: For a few CEOs I've spoken with, I've heard this variation, "Yeah, I thought about it long and hard and decided this was what I wanted to do." There's a pause, "And then I spoke to my family." So that is my question, what did your loved ones think of this idea?
• 3:08
  Eduardo Bravo: That I was completely crazy and that I should not do it. And, you know, I was 40 when I left. I was, you know, Vice President of the whole of Latin America. Probably as the youngest vice president at Sanofi-Aventis at that time.
• 3:21
  Eduardo Bravo: Very well regarded, and I was joining an 18 people team in Spain in cell therapy. I mean, it was like, What on earth are you doing? But you know what?
• 3:28
  Eduardo Bravo: Really, I wanted to be calling the shots, and I wanted to run a company my way, which I had the opportunity of doing with divisions in the past, but not at the time of making the decisions. You look that you are very young, but still, you know, only 20-25, years ahead of you.
• 3:47
  Eduardo Bravo: So, you know, staying longer, then it would have been impossible to move. And then some people have done it, so probably it was the wrong assumption. But I thought like, you know, come on, I'm young, I have the opportunity. Let's jump, and you can always go back. It was much tougher than what I anticipated. So let's, let's be realistic here. I think that, you know, there's all the glamor of the things that I was looking for was great, but, you know, it's also very challenging when you don't have the resources that you're used to having and you deal with a very, very small team. You know, sometimes, in my case, it was not sophisticated investors. It was not an easy landing.
• 4:26
  John Simboli: Do you remember any, either in the first go round or here Citryll, any things that were a surprise as far as what it means to be the leader of a biopharma company, rather than be a member of a large company?
• 4:37
  Eduardo Bravo: In pharma, you have a structure. I mean, the good and the bad is that you are a small piece of a huge machine.
• 4:44
  Eduardo Bravo: The machine takes care of everything, most of it. The bad part is that, you know, you feel yourself as just a non-contributor, And it depends, some people are very happy like that. But, you know, I felt like, you know, I would like to to understand how little you know, and you need to see whether I can make a difference. And moving it was not Citryll it was Engitix in Spain, a very, very small biotech in the cell therapy space where, you know, we were making the calls. I mean, it's like, we're going to go for this indication, and it's us. And, you know, remember telling at that time a very inexperienced management, team guys, we have the money because we've been given the money. It's on us. You know, if we fail, we cannot blame anyone. You know, we're making the calls, we're calling the shots. So it's on us. And you know, we made some good calls. We made some sub-optimal calls. We learned a lot all together. And, you know, at the end, it was a successful story.
• 6:14
  Eduardo Bravo: make calculated bets. And sometimes you know, I remember, you know, but not only in the team surrounding the company, but also at the board, we had Ed Holdener, who was the ex-CMO of Roche, which I will have all the respect for him, because he was always saying, like, we're doing an experiment. I mean, at the end, you know, we're testing a hypothesis. So a negative clinical trial is just that, you know, the hypothesis was not correct. Of course, it's not what investors want, is not what the management wants, but this is it. I mean, you're given the money to run a hypothesis, and the hypothesis, with all the information you have, is the best possible hypothesis. And I keep also telling my teams over and over again that our job is to reduce all the risk to the technology risk. You know, if the product at the end fails because the hypothesis was wrong, the mechanism doesn't fly, it's out of your control.
• 7:11
  Eduardo Bravo: If you choose the wrong indication, if you go to the wrong patients, if you design the wrong clinical trial, if you do the CMC wrong, if you cut corners that should be not cut, if you go the wrong way in the regulatory path, that's on you.
• 7:26
  Eduardo Bravo: That's what management is supposed to be doing. It's like, okay, take away as much as possible all the other risks, and investors should be faced with the technology risk, which you cannot control.
• 7:37
  John Simboli: As you consult with your team to try to get the most information, and then in the end, you're responsible for making that choice terms of direction, how do you deal with the fact that sometimes that is the wrong decision? In other words, one CEO I spoke with said, you know, I had to get over my fear of making a wrong decision and realizing I might likely be able to correct it down the road. So I guess, what I'm trying to get at is, how do you separate the fact finding with the team from the I'm going to make the choice, and I might be right and I might be wrong?
• 8:10
  Eduardo Bravo: Well, I think that we all know that every decision is a guess, and you're just taking your best guess. And I truly believe that the best people are taking those decisions are the ones that have no fear in recognizing very quickly that it was the wrong call and that you can, most of the times, change your mind. And again, I am a strong believer that, you know, you try, you make a call, you try, and you should be analyzing very quickly. You know, does it make sense? Is this improving or not?
• 8:39
  Eduardo Bravo: And if not, let's try something else. I love copying as well, you know, I you know, every time we recruit someone and say like, well, especially the first three months, because after three months, people become, you know, part of the company. You know, the first three months, you look at things with critical eyes, usually when you arrive into companies like, well, if you see anything that we're doing, that you've seen anywhere in your career done better, faster, cheaper, tell us. Because, you know, here there's no right way of doing things. We will do whatever. And if there's a better way, we will try. And if it works, we keep it, and if it doesn't, we go back. But, you know, not changing or being obsessed with your way of doing things, I think, is the recipe for failure. And sometimes the bets are very long term. I mean, when you start a clinical trial, you cannot change three months later. It's like off . . . It was the wrong indication. I mean, you're probably committed.
• 9:33
  Eduardo Bravo: So you also need to understand that there are certain decisions where you need to spend a lot of money and energy and time making sure that you make the best possible call. But also, you know that there's a lot of decisions where you should just take it, because not taking a decision is a course of action.
• 9:49
  Eduardo Bravo: Inaction is pretty bad in the majority of the cases.
• 9:56
  John Simboli: Coming from a non-science background, to lead a scientific company brings up the question, earlier in your education and your life view, what path did you see yourself on, if not this one?
• 10:09
  Eduardo Bravo: Definitely not this one. You know, it's amazing how many times I tried to move out of the pharmaceutical space despite, you know, my family is a family of doctors, so I'm, you know, I've been very close. But I have an older brother, and probably, you know how those things go, my older brother then decided to follow my father's steps as a doctor. So then I decided I'm not going to be a doctor as well. And I was good at numbers, so I like math, and I like the money, so I decided I'm going to be a banker. And, you know, I could not find a job as a banker when I wanted to do a training. And through the priest of the of the church of San Luis De Los Franceses, in Madrid. And the priest was a friend of my mother's friend, and he went to school with the head of HR of Pierre Fabre in Paris. So I ended up as a trainee in the oncology department of Pierre Fabre.
• 11:06
  Eduardo Bravo: Never thought that I was going to be there, but I wanted to learn French because I wanted to do INSEAD so like, who cares? I do this, and then I will go into banking. Then I got a job as a banker in London one year later.
• 11:18
  Eduardo Bravo: Like, that's what I want to do.
• 11:18
  Eduardo Bravo: So here I go, except that I resigned from from Pierre Fabre, and then found myself that, you know, I needed a work permit because Spain was not part of the EU. Had to go back to the industry. And then went to INSEAD, and I wanted to get out of the industry. But then at INSEAD, I really made the conscious decision—what I like is to manage teams. I don't care the industry. I want to have teams, and I want to be able to manage through people. That is what I like, that's what I think that I do. Well, that's what for other people to judge, but that was my internal thinking. And I went back to () at that time because they offered me the biggest team of all the jobs that I had when I left. And I was super happy with that, and that was back in the industry.
• 12:07
  Eduardo Bravo: And, you know, 30 years later, here I am.
• 12:10
  John Simboli: At INSEAD, what realization did you have about managing teams? What did you find out about yourself that you realized I like this, and I'm good at this?
• 12:19
  Eduardo Bravo: I've always liked it, and I had a very small team when I left for INSEAD, but it was this idea I really enjoyed all the management. I saw, that I was attracted to that area, that's the area where I was reading the most. I felt that I was pretty natural, but I had the option of going into bigger jobs that were usually better for MBAs, which are staff positions, and I was not attracted to that. I was not attracted at that time by the money or the position. I was
• 12:48
  John Simboli: If someone were to ask your teammates, what is it more attracted to the, this is what I like. I want to do this.
• 12:57
  John Simboli: that makes him good at managing this team or leading this team?
• 13:00
  John Simboli: What do you think your colleagues would say?
• 13:02
  Eduardo Bravo: Yeah, I think that I bring a lot of focus and direction, but I leave a huge amount of liberty to the people below. So you can say that I do not micro-manage, and I'm a fanatic of pushing people further and further. I'm good at challenging the people to keep growing and, you know, also keeping calm when things do not go well. I'm very good at keeping people informed as well.
• 13:26
  Eduardo Bravo: I mean, for me, communication to the people, they need to know what you're doing and why you're doing it. That's my job as a leader, is to challenge the people to think. You know, if they cannot convince me, Wow, I become nervous. So I'm a pain in the neck asking, but if I get convinced that I'm like, Okay, this is under control, I'm happy with that.
• 13:51
  John Simboli: When you get that, just tell me about Citryll, and you realize you only have a very short period of time, how do you
• 13:58
  Eduardo Bravo: We're a private biotech company based in the Netherlands that has a monoclonal antibody targeting a very new mechanism of action that hopefully will be able to solve a lot of the inflammatory diseases which are common to many, many diseases in the world.
• 14:19
  John Simboli: Can you describe what that gap is, and was? In what ways were patients not being served, that was needed for a company like yours to come along?
• 14:27
  Eduardo Bravo: If you look at the immune mediated inflammatory diseases, and despite the incredible advances that have happened since biologics arrived, I mean, I can think rheumatoid arthritis and the arrival of Humira, the anti-TNFs, then the anti CD 20s, the Jak inhibitors, the IL 6.
• 14:46
  Eduardo Bravo: You go to determinative, super active, and now with the appearance of the IL 17s. So psoriasis, I mean, you name it, all these diseases. If you look at the transformation over the last 20 years, it's pretty.
• 14:58
  Eduardo Bravo: phenomenal. Now the problem is, if you look at where we are, there's, I would say, around 40, which is a pretty amazing number, 40% of the patients that are not adequately controlled with existing therapies. So, you know, there's, there's been a huge improvement, but the gap is still fantastic. It's like, you know, probably in oncology, you know, if you look at where we were, where we are, but you know, what remains to be done?
• 15:29
  Eduardo Bravo: Well, I think that inflammation is a little bit the same, and people have been looking in a very precise way, looking at all the, you know, downstream, every pro-inflammatory cytokine and marker, and how we can. You know, these NETs were discovered 20 years ago. So we're talking yesterday for the pharma industry. You know, neutrophils, which, you know, I still have, my CSO that says, when he was at GSK, if things were touched by neutrophils, they would just shut them, you know, because no one understood neutrophils. It was part of the innate immune system. We don't want to mess with them, because they are the first responders to an issue in the body. So when those NETs were discovered, now, finding a way of, because we have the beauty of this dual mechanism,"A," being able to inhibit additional NET release, so we can stop new NETs being released. And very importantly, and we believe is the most important of the two, we can help clear the accumulation of NETs in the tissue. So suddenly, if our hypothesis today, published by many, many groups in many diseases, is that indeed NETs are the initiators and the key components of the inflammation, and we can target those, we believe that we go at the very top of the inflammation cascade, and therefore we should have a much broader applicability than the very specific cytokine targets.
• 17:10
  John Simboli: How would you describe the function of the NET, and why is it foundational?
• 17:15
  John Simboli: Do you find yourself still fielding questions, especially
• 17:15
  Eduardo Bravo: So NETs have a pathological, a very important mission. So, you know, neutrophils, which are the most common of the white blood cells, are the first responders to a host attack to the body. And you know, neutrophils respond in four ways, one of which is this NETosis. So it's they sort of explode, if I can say explode, and release their internal content, these web like structures that have, you know, DNA. And those actually are capable, that's the reason why they are called traps, trap these foreign pathogens. And after they have trapped them, they are cleared by macrophages.
• 18:00
  Eduardo Bravo: That's the way they should work.
• 18:00
  Eduardo Bravo: And we have NETs all over, small amount, because there's always something going on in your body.
• 18:10
  Eduardo Bravo: Now, what has been discovered is that in some genetic preconditions in some patients, people have either neutrophils that NETose too easily, or you have an overproduction of NETs.
• 18:24
  Eduardo Bravo: One, you have too manyNEs, those NETs accumulate in the tissue and generate tissue damage.
• 18:29
  Eduardo Bravo: Because the NETs, apart from, you know, trapping those things, release a lot of pro-inflammatory cytokines. So if you have a continuous release of NETs and accumulation in the NETs, you are actually creating an inflammatory environment. So in a normal, healthy person, you will have some neutrophils netting. And these NETs being healthy for your body, and they will just, you know, clear your pathogens, and they will be eaten by macrophages. But if at some point that regulation is altered, then you have accumulation of NETs, and then an inflammatory process starts, and that inflammation goes into tissue damage, and then you have from chest arthritis to COPD to cardiovascular disease to now, even people are saying this beta in Alzheimer, these plaques are actually coming because of NETs.
• 19:30
  Eduardo Bravo: We have now doctors saying that, you know, some of the mechanisms of resistance of tumors have to do with presence of NETs in those tumors. So we're not going in to cure everything. I mean, I think that we need to be very realistic. But what is amazing is that something that was unknown 20 years ago, today there's plenty of literature and every day there's new literature linking NETs to more diseases, all of inflammatory component.
• 20:03
  Eduardo Bravo: Now, the link that we need to do, and that's the hypothesis, is that by reducing the NETs, you will have a clinical effect.
• 20:17
  Eduardo Bravo: The question that I get the most is like, How sure are you that the NETs are the cause and not the consequence of the inflammation? We call it informally, the chicken and egg problem. Well, I think that we have more and more data that we believe shows that they are the initial and that, you know, they are a cause. Clearly, there's very little or no data to show that you can have a clinical effect by touching NETs. That's what remains to be seen. We've done it in animals, but now we need to do it in patients. No one has been able, I mean, there's been some older tries.
• 21:01
  Eduardo Bravo: The NETs are created when through the PAD4 inhibitor, enzyme. And I don't know if you remember, but a few years ago, this PAD4 became super hot, and BMS, I think, acquired Padlock.
• 21:17
  Eduardo Bravo: So it was, you know, there was a couple of very big acquisitions, and two or three big pharmas had these PAD4 inhibitor programs, because it was a small molecule, and you could actually eliminate NETosis by not allowing these NETs to explode inside the neutrophil. So that was the idea, you don't allow the decondensation of the DNA, and therefore the neutrophil does not explode. I still think that they will be missing the clearing of the NETs, but that's a different story. That was the idea. So there was a lot of interest. Now, the problem with those small molecules is that PAD4 is an intracellular target that touches many other things on top of this, you know, DNA, the condensation of the neutrophils, and therefore are very toxic. There's some people now, AstraZeneca has an antibody against PAD4. So it shows that some companies have not abandoned it completely. But it's very, very early stage, but it's still no one has been able to target these NETs. We're the first one. So, you know, people were interested. We've seen some big pharmas that have come to us and like, wow, we really like this approach, we really like this NET idea, but we've never been able to target. You know, those pharmas, some became investors, some are probably are looking into the data, will be looking into the data. Because also, when you go with a new mechanism of action, there's still a lot of unknowns. Is the dose sufficient, you know, what is the right regimen, what is the right indication, what is the right patient, what is . . .
• 22:55
  Eduardo Bravo: So I understand the risk associated, but for me, this is like an anti TNF Alpha when they arrived, a PD-1. I mean, I think that this, if our hypothesis is right, this will unlock a new category of anti-inflammatory I will call it like this. Probably the phrase agents.
• 23:13
  John Simboli: At very beginning, you were saying that one of the attractions for you about Citryll was that, in a sense, that I will hear the most would be, we remain to be convinced it's a simple idea. It's not hard to grasp, not easy to find out if it's right or wrong. But the concept, I think you said, that by reducing NETs, you will have a clinical effect. That's was not difficult to grasp. My guess is that an investor conferences and other places where you're talking to sophisticated audiences, that there are times when people hear the reason why we're doing two clinical trials. In two clinical what you're saying, what you've been saying to me over the last half hour or so, and and decide that they see you as this kind trials, and if it works in both, but we will need to show it. No of company, or someone else sees you as that kind of company. You know, maybe it's who knows what it might be? Can you describe one dares to dispute that you can give a corticosteroid for what categories of misunderstanding there are about Citryll and then how you go about saying, No, we're 100 indications. What if this was the 21st century actually, this is what we're about?
• 24:00
  John Simboli: corticosteroid without the side effects of the corticosteroid?
• 24:08
  John Simboli: If really NETs are this important, and we could really eliminate excess NETs in the body? That's the maximum. Yes, but I don't think that RA is the only area. We're doing RA, How does the Citryll platform and pipeline because it would be very easy for pharmas and investors to understand that there's not a single compound that works only in RA. If it works in RA, it works in at least 10 indications. Once you've crossed that bridge, a lot of people express your vision for the company?
• 24:56
  John Simboli: will see this very differently, and that's reason why we went there.
• 25:08
  Eduardo Bravo: The vision is to bring something to the market as quickly as possible that really makes a difference for patients.
• 25:17
  Eduardo Bravo: And you know, if it's a, you know, the new corticosteroids of the future, fine, if it's a super-targeted approach for a sub-population of HS. But we need to find out which patients will benefit and how quickly we can get the compound out for those patients. That's my goal.
• 25:36
  John Simboli: Many people listening will have a working understanding of what RA is. Can you help with describing HS?
• 25:44
  John Simboli: What do patients have to deal with? What's their life like?
• 25:48
  Eduardo Bravo: Hidradenitis Suppurativa, which is the horrible name, and that's reason why it's now called HS. And three years ago, no one knew what HS meant, not even in our sector. But now the arrival of the IL-17, Cosentyx and BimZelx and others in development has transformed the market. So now all the investors, everyone understands HS. But HS is a neutrophilic disease in which you have an infection that usually starts n the follicle. I would say, gets out of control, and you end up with, in the armpits, in between your legs, under your breast, in the areas of friction, you end up with huge abscesses and scars and tunnels and superation, which means that smells, I mean, it's very, very debilitating. You don't die of HS, but people have, you know, a lot of difficulty in living with it. It takes ages now, hopefully it will be quicker for GPs to recognize it and to treat it correctly. And now, with the IL-17 is starting to change, but up until now, with very little effective treatment available, so patients had to endure those therapies going through surgery when the area was, you know, too damaged, and so you have scars, you know, you don't want to show your body. I mean, it's a tremendously debilitating disease.
• 27:16
  John Simboli: How was it that Citryll chose to be located in Oss and the Netherlands?
• 27:20
  Eduardo Bravo: The company was started in Oss. It's where Organon was founded. And you know, that's where Keytruda was discovered, because Keytruda is originally an Organon compound, is where the PTK of Acerta, Acerta is there. So there's a couple of very big drugs already that have come out of of the research in Oss. There's probably 50 or 60 biotech companies there, So it's a very small location, but there's like a small hub. I think that that's what is impressive about the Benelux in general, is, you know how good they are at moving compounds and companies and funding them, and you know, the science is great, and the founders are great, and there are teams there. And so, you know, all my respect for those countries, I think, in how they are developing the industry.
• 28:11
  John Simboli: Eduardo, thanks for speaking with me today.
• 28:14
  Eduardo Bravo: Thank you, John.
• 28:14
  Eduardo Bravo: It was a real pleasure.