John Simboli:
0:00
Today I'm speaking with Ivo Timmermans, CEO of Pleco Therapeutics, headquartered in the Netherlands. Welcome to BioBoss, Ivo.
Ivo Timmermans:
0:08
Well, thank you, John, it's a pleasure for me to participate in your podcast.
John Simboli:
0:13
Ivo, what led you to your role as co-founder and CEO of Pleco Therapeutics?`
Ivo Timmermans:
0:17
I would say it's actually a matter of serendipity. I have worked for the last 30 years in pharma and biotech companies in various roles. My background is that of a medical doctor, and shortly after I graduated, I got involved in clinical studies with HIV compounds. And soon, thereafter, I started to work in a pharmaceutical company developing products. And over the years, I've had several roles. And I would say about five or six years ago, I met an oncologist in Chicago at ASCO, which is the largest oncology conference in the U.S. And she introduced me to a concept that is now the basis for a company. And at that time, I had a role in a company that was more a logistics and distribution company. So there was not really an opportunity to follow up on that. But when I left that company, I contacted her again, and we started talking. And I realized there was quite a lot to the concept that she was exploring. So we decided to work together. I contacted a few former colleagues, and assembled a group of people who I knew had certain expertise. And about four years ago, we started with four founders. And that is still the core of the current business.
John Simboli:
1:39
Had you considered in that early stage, when you became aware of the scientific foundation for what could be the company, had you considered taking that idea to an existing pharma company and saying, would you be interested in bringing this idea in house?
Ivo Timmermans:
1:55
I did, yes. But the thing that you should know is that traditional pharma companies are also slow institutions. And if you have an idea that we have, which is pretty out of the ordinary and pretty outlandish, then it is not easy to amalgamate that with the routine business that a regular pharma company has. It's much more practical to have a startup company where you can be adaptable, flexible, where you can make quick decisions, and don't have the the rigid structure that would slow things down. And actually, about 10 years ago, I got involved in the world of the small startups, spin-offs from universities, and also the partners that I have been working with, and that have now joined, they're also quite skillful, and creative in setting up new organizations, new ideas. And that is, I think, to develop something completely novel you need a fresh organization, and one that can move whatever way it wants, and be very agile and flexible.
John Simboli:
3:09
It's a big step to try to start a new company. It's also a big step to decide to be the CEO, when you're coming from a background as a physician or scientist. How did you go through that process and say, yes, I think I'm the right person to do this?
Ivo Timmermans:
3:24
I think if you ask many CEOs, which you do, you will probably hear that they somehow roll into their job on most of the occasions. Not somebody who was born or who thinks, when they're 16 years old, I want to become a CEO of a company. So it is usually when you get together with a few people, and I was the one who took the initiative, that I was the one who started to coordinate it. And then somebody needs to play the CEO role. And that is usually the person who has the oversight and can coordinate it best. I must say that over the years, I've had several roles. My background is that of a medical doctor, I started to work in pharma as a clinical research physician, doing actual trial work and then gradually I rolled into the more organizational roles like medical director of a company running medical departments, getting more involved in the strategic part of the business. At some point I did a Master of Business. So I also decided to add something to my business acumen because I felt that was a nice fit to also looking at things from more angles than just the medical. I should say that after some 30 years in the business, it's actually nice to be in a position where you can also take decisions yourself and and not having to ask permission for every step you take. I must say that is the positive part of it. The downside of being CEO is that you have to solve issues every day. And then every every thing that is not certain or that is problematic always comes comes to you in the end. So it is an interesting role, I should say. And so far I'm enjoying it tremendously, certainly with the team that that we have put together.
John Simboli:
5:26
How did you decide that what you could do at the new company could be something that really couldn't be done anywhere else? Was it a whole new way of thinking about metals in cancer?
Ivo Timmermans:
5:37
Yes, yes, that is true. Let's say the underlying concept is that metals play an important role in cancer, in the development of cancer in the perpetuation of cancer. And the underlying idea is that man is exposed to all sorts of metals throughout life. And over time, this accumulation of metals in the body can create problems. Obviously, we know that acute intoxication of metals is toxic, and poisonous, we see a lot of professional intoxications and people suffer from exposure to chromium or to cadmium, or through professions. But the chronic exposure of people who are exposed to metals in everyday life, there's not much known about this. The big picture started only in the last few years. And it is a credit to the oncologist I met that she looked at her leukemic patients, and she saw an elevation of metals, of toxic metals in the blood of her leukemic patients. And also, she saw that the extent of the elevation was associated with long-term outcome, with survival. And that prompted the question, can I use existing products or fine tune existing products and see whether they have an influence on the disease progression? And that is a concept whereby you, on one hand, have a completely new approach, a new idea, you work at the crossroads of physics, of biology, of artificial intelligence of simply the clinical treatment of patients, which is very complex. And on the other hand, you have to deal with a completely new therapeutic area, where nothing is explored—the extraction of metals to treat diseases, very poorly understood. So you work in a new area where you've got some existing products, off the shelf, which are actually crude tools. So we are fine-tuning those, we are looking at sophisticated ways of putting products together. So there is a very creative element that you need to do there and work with people in formulation. The emergence of such a new product and product line is something that amalgamates a lot of expertise and brings a lot of things together. And typically, that works best if you have a young company where you've got a few people who are very creative. I've got a few very bright colleagues who, who can put things together and connect things and ask the right questions. Automatically, that brings you to certain strategies that only can be done in a structure where you're very small and nimble. Let's say from the invention, and from the development of this completely whole product line, follows the structure of the company. And that's typically a small company with a lot of specialists around it.
John Simboli:
8:54
When I hear those words, creativity, interdisciplinary, multiple indications, potentially, I think that as a CEO, the job of figuring out what it is you're going to pursue, and specifically how you're going to spend your time each day, that must be its own kind of challenge, because in a sense, it's limitless. So how does a CEO go about figuring out what they're going to attack on a daily basis? Is that something you know, or is that something you've learn?
Ivo Timmermans:
9:28
I think over time it has developed, I was in the lucky circumstance that I brought in two veteran colleagues. One of them is very good scientist, who, as it appeared, did his PhD 30 years ago on the role of metals in chemotherapy and the effect of chemotherapy. And the other person is a senior business executive who has a network in industry and a lot of marketing experience. So these are the two veteran colleagues who helped me define what we should do on a daily basis, And that also takes a lot of burden from my shoulders because I have all this flow of ideas and people bring to the table some good approaches. The fourth founder is a legal specialist because if you start a company, you need to have somebody on board who can deal with all the administrative parts with all the contracts, all the liaisons with external parties. And I would say that over the last four years, the priorities for the CEO have changed. And on one hand, it is looking at what is possible in terms of indications. And then my medical background helps and the fact that I've been involved in drug development, so we're looking at the ease of development, also looking at niche indications where you can make a big difference. And also indications where there's high unmet needs for patients. So we tried to make a selection of that. And we started with the indication of acute myeloid leukemia, that is also the indication where most of the work was done in research institutions. But we're now looking at lung cancer, at pancreatic cancer. So we're looking at setting up these small models, and seeing whether we can extract from the models, the information that we want, that justify further developments. So that is actually a big part of what I've been doing in the last four years. On the other hand, as a startup, large parts of the work of a CEO goes into fundraising. And that can be a nightmare, because especially if you have an outlandish concept, as we have, which doesn't treat patients based simply on a product that attaches to a receptor or product that deals with vasculature of tumor, we have something that's completely new, and it's difficult for VCs to, to understand that and to find comfort in that thought. So we had to put quite a lot of effort in fundraising. But as a CEO, I get up and I never know how the day's going to evolve. I hope that some days when I when my agenda is clear that there will be quiet and I can catch up with some work. But these often turn out to be the most busy days. And sometimes we have acute things to solve. And that's, that's the charm of startup, I guess everybody will tell you the same. There's little little routine, put it that way,
John Simboli:
12:48
Through this experience of being a CEO, what have you learned about your management approach that says this defines how you work?
Ivo Timmermans:
12:56
Well, particularly in a small company, the traditional approach of some one person dictating to others what they do is not very helpful. And if you're starting with a group of four or five people, it is sitting together, sharing the responsibilities and the task. And ultimately, I need to take the final say, or summarize it. So I see that role as more a participative way of managing. But I think that is also the management style I like most. You bring people on board because they contribute, come with ideas. And then the task of a CEO is actually to challenge and to ask the right questions and make sure things are discussed and that you get in the end, not everybody can have their way, but that you get a good consensus and a good understanding between the team members. So I see the CEO as more sort of chairman who facilitators, somebody who supports where he needs to try to get a feel for where people need help or where they could do with some extra external advice. So it's more that role, and I think that, certainly, in a startup is the only way you can work, in my opinion. I must say, John, that also I had the pleasure to appoint some very senior colleagues, and they are no walk-overs. So if they have an opinion, we need to listen to them. So sometimes, for me the challenge is to limit the meetings to the hours that we set for them because a lot of things raise new questions, etc. But, certainly it's important that everybody has their say and the emphasis is also if there's an interesting scientific question or a question on research strategy, then the head of R&D obviously has a heavier say and more knowledge of those topics, so the others ask questions. But in the end so far, we've always been able to come to the common way forward.
John Simboli:
15:14
Can you recall when you were a young person, maybe eight or nine or 10, whatever would be appropriate, what that self image, you had no doubt based on what you thought your parents thought you should do when you were a grown up? Do you remember that? Does that have anything to do with what you're doing professionally?
Ivo Timmermans:
15:30
Not really. But I can still remember what I liked to do when I was that age, I found it hard to choose between selling ice creams, and becoming an astronaut. So these were my two ambitions when I was eight years old. And it was also the time when mankind traveled to the moon, so that was a very exciting period. So that was, for a long time, in my mind. And then I later switched to I want to become a helicopter pilot for the safety and rescue services. So there was something in there that's vaguely is related to what I'm doing now. But I've always had some fascination for these professions. And at some point, I decided to go to medical school and I never looked back.
John Simboli:
16:25
Do you recall a moment either as an undergraduate or graduate or even well into your medical training, when you had the realization that I have fallen in love with something, this idea, this discipline?
Ivo Timmermans:
16:39
A few occasions, yes. I thought medical school was divided first, a few years in a sort of theoretical part where you get a lot of knowledge, which is not always practical, but I loved the the latter years where you treat patients and get into contact and have time to sit down with people. And it's nice to hear these stories, I can still remember one or two patients that made a large impression on me because of their diseases and what it's meant to them. Especially when I did my internship in the department of oncology that made made a big impression. I also loved my months in pediatric wards. It's amazing how these dynamics go with families and people affected by the disease of a child. So I had some things where I thought I'm in the right profession. Although I never fell in love, really, with the clinical work, because I thought that was quite repetitive. As a doctor, when you examine a patient, you ask your routine questions. And if they say no, at question number three years, two more questions. So you get into a routine of going on autopilot, put it that way. And at some point, I got involved in the effect of medicines. And I never thought that was so fascinating. When I just graduated, I was working for an internal specialist, who had a cohort of 70 patients with AIDS. And that was the early 90s. So that was precisely the time when that was the challenge to find new medicines for that. And a company called Burroughs Wellcome developed the AZT retrovir that was the first effective anti HIV compound. And I got somehow involved in clinical studies, I saw the effect. And then I thought, well, this is the real thing. If you develop medicines, you really make a difference.
John Simboli:
18:55
It must have been an interesting pivot to, on the one hand, connect with patients on an individual human level and realize how vulnerable they are and how much they need you as a physician, on the one hand, and then on the other hand, realize I can only reach one patient at a time. It's kind of a riddle, whereas what you're doing now potentially can affect the lives of many patients and, still, profoundly, right. I mean, if things work out the way you hope?
Ivo Timmermans:
19:24
Exactly if we're looking at the first indication, let's say acute myeloid leukemia, worldwide there's about 1 million patients who suffer from that. And over the last decades, there has been some minor improvements but not very much. And it still has a pretty poor prognosis. Also, for that reason, it is very satisfying to work in that area and see whether you can improve something in niche areas where there's a lot to be discovered and improved. To us, that's an extra motivation to do that.
John Simboli:
20:06
So when people say, Ivo, who is Pleco Therapeutics, what's your typical answer for that?
Ivo Timmermans:
20:13
We are working with a completely novel concept in that we start to appreciate the role of metals and the way people get contaminated over life with metals, and that they play a role in disease, and the pathophysiology, and also in the maintenance of those diseases, and that we try to treat it. A whole new way of approaching medicine by looking at the underlying causes of cancer. So not looking at mechanisms or targets but, certainly, removing the toxic elements in microenvironment where these metals cause damage to DNA, to stem cells that multiply. So we're tackling the underlying cause of cancer. And that is something which only a few companies are really doing. So we have a completely different approach that is different from any other company. And it's even so unique that we had to design our own preclinical models to do that. Because if you have a typical development of a pharmaceutical, you start with models in cells, or on the drawing boards in cells and smaller animals, and then later into humans. If you order cell lines for animals, for your laboratory studies, they're not contaminated with metals. Actually, you can catch a few rats in the sewers of Manhattan, you wouldn't know what they're contaminated with. But that's sort of mimics the human situation. So we order clean rats and mice, but we have to contaminate them with a mixture of metals and make sure that mimics the human situation. Because only then it makes sense to test the effects of our drugs. So we're doing something completely different, how to design our own models that were not validated yet. And now we've got a reproducible model. So we're doing something that is completely out of the ordinary. And for investors, I would say 10 years ago, 15 years ago, everybody talks about microbiome, and nobody understood it. And now it's the biggest thing in drugs and pathophysiology and immunotherapy. The first companies in immunotherapy had the biggest problem finding funding, because nobody thought how it would be possible to trigger and to fine tune the immune system so it would start to remove cancer cells. So sometimes the concept is in its infancy, and then you have to convince people, what's the significance it may have. But we're looking at metals, the role of metals in certain cancers. I imagine that there must be some investors who hear that and We're also looking at the role of metals in some neurodegenerative diseases. Metals have affinity for some body tissue, like bone marrow is one of the preferential places, but also nerve cells. And we know that diseases like Parkinson's, Alzheimer's, ALS, that there are quite a few publications where people reported elevation of metals in these tissues. And so that's also on our radar to have a look at that. So, actually, we are exploring something which is fascinating. It's a journey, it's something that opens up opportunities. And that's how we try to explain it to investors. And if they sit long enough and try to hear our story, most of them get fascinated by it. And it is sometimes difficult to summarize that in a very short span of time, if you got to 10 minutes and you want to explain your business model and the background of it, then that is almost impossible. their instinct may be to say, what category can I place this company into so I can begin to weigh whether I want to invest or not. Unfortunately, that sometimes can be part of the deal, right? When they do understand that's, great because it leads to the next conversation. When they don't, and they put you into a different category than the one that that Pleco is in, what does that category tend to be? And then how do you bring them back around? It is difficult that we don't fit the standard definitions for categories because we are developing therapies that remove toxins from the micro environments and by doing that chemotherapy becomes more efficient again. So we're using that as a supportive therapy to make other therapies work better, which is an extra complexity, of course if you develop it. It's not we do "A" and then "B" happens, and then "C" follows, so it is a different category of drugs, certainly. It falls into the category of supportive co-therapy. It is compatible with all the therapies that are available but we are doing something which is difficult to describe. We call the category Plecoid(TM) agents. And we've also got a trademark for that name. When we looked at a company name, we found that many names were already taken. Certainly if you go to Greek and Roman mythology and all the animal names, they are taken, so we ended up with the plecostomus fish, which is a tropical fish used in aquaria to clean the algae from the insides of the glass and the stones. And that's actually the analogy with our drugs. So it's named after the plecostomus, suckermouth catfish in the UK, I'm not sure what the U.S. equivalent is. But it cleans the aquarium. And that's actually what represents what our products are doing, cleaning cells from the insides.
John Simboli:
26:12
When I saw that on your website, that seems like an apt simile, because it's also organic, it's also working via a natural process. Do I have that right?
Ivo Timmermans:
26:23
Yes, we remove inhibitors because metals stick to DNA, they make it more difficult to read. They stick to biomolecules, to proteins, make them more difficult to work. And some of these proteins can also trigger cell death when the damage is too great. So it's important that a number of these biomolecules function properly, and removing metals repairs, actually, the natural function in these cells. And that's also part of our research, is also to elucidate that process. And we have a much better understanding now after a few years of research how it works. But basically, you're right on that, John, that is the way we try to restore the natural functioning of of the system.
John Simboli:
27:14
Let me come back to that pigeonholing question, I just want to explore that one step further, Ivo, I'm just guessing, because for most of the companies I've worked with, it's a step they have to pass through where you get misperceived as category X, and you're really category Y. And I know that you're in a new category, so it makes it much more complicated. But I want to ask the question, surely there must be a pattern that you've encountered of, you think were "this" based on what I've told you, but were "that." What is it that people would misperceive?
Ivo Timmermans:
27:51
I think what they misperceive is that they probably perceive that we do something with metal toxicity, that that is the first thing people hear. And then they associate it with acute accumulation. And what they probably miss, and that is actually the whole basis for our concept is that we live in a different world where the whole chemical environment has changed over the last 200 years. And that's actually what we're looking at is the chronic accumulation of metals. To give you an example, if you work on the street, you inhale lead, from traffic. If you work and you sit in office, you are exposed to cadmium, it's in batteries. If you eat crab fish, it has traces of mercury. So involuntarily, you accumulate metals. And 200 years ago, the industrial revolution started and only and, shortly thereafter, certain diseases were reported more frequently, like Parkinson's is a disease that was reported for the first time in 1830. And that was about 30 years after the Industrial Revolution started. So if you look at that, and also analyzing lead content and bone marrow from today's man compared to prehistoric man, we've got about 100-fold more or lead content in our bone marrow. So it is obvious that when that reaches certain thresholds and exceeds it, that it can lead to abnormal behavior of tissues and cells. So we're looking at a whole concept and that's what we try to get through. People associate metals with, okay, you need them for certain biological processes as catalysts, as whatever. And sometimes people get acutely exposed, but our underlying thought is that the whole environment has changed and that has caused a number of diseases and we also live twice as long as we did 150 years ago. And the half-life of toxic metals in the body is very long. So there's no doubt that we see a number of diseases when we get to be 60 or 70 years old, that were not there 100 years ago, that this is related to some external factors, to our mind. So what people don't see is that bigger picture of things. And that's what we're trying to convey, that message. And that's quite difficult to get that through.
John Simboli:
30:34
How does the pipeline that you've developed, reflect your vision for where the company wants to be, and what the company is going to be?
Ivo Timmermans:
30:41
We started off by looking at what compounds are available that have the characteristics that we are looking for. And if you look at the type of agents that we are exploring, which is called chelating, agents, they chelate, in other words, extract metals from the body. Then there are quite a few agents available, not always as specific to the metals that we want to extract, not always have the broad spectrum that we like to have, because we know it's many different metals. So we've started to make a selection of the compounds that are known. And if you look at Wikipedia, and you look at the list of chelating agents, there's 160, or 200, agents that are mentioned there. So we started by selecting and bring it down to the agents that are known to man, that were tested in man, and then you come to a dozen or so and we brought that down to an even lower number. So we're looking at known agents, we're looking at modification of those agents, because you can change them. Also drawing board exercises, you can change and modify the molecule somewhere to give it better pharmacokinetic properties that you want to. So we're looking at also analogs of these agents that were once designed and not taken further to the clinic. So we have a whole range of known agents, agents that we want to modify, and agents that we know existed once, but we're not tested properly. And on the other hand, we have a lot of clinical indications where we want to have a look at. We look at leukemia, because that's the starting point also of the investigator who came up with the concept. We also looking at small cell lung cancer, which is an aggressive subtype of lung cancer associated to smoking. So you can imagine that through the inhalation of smoke, that metal deposits in lung alveoli, and that causes local inflammation and triggers cancerous processes. But there's actually five or six cancers where you can if you do literature search, where you can find an association with metal deposition. So, to us, it's simply a matter of getting the resources and funding, over time, to explore all this. Now, what we are doing, in addition to trying to set up tests in patients, we're also looking at bio-banks, because there's a lot of material from patients who have suffered from a disease and we're looking at the metal profiles that we find, so get a confirmation of what we saw in leukemia, and see whether that same profile of contamination also exists in other diseases. And if that metal profile, for instance, of lung cancer could be different metal profile than in leukemia, if those profiles match, you can easily argue, well, if we develop product A, it could be efficient for indications, A and B. But if there's a mismatch, or if we see a different emphasis in the profile, different metals that are involved, we might need another compound or combination of compounds to tackle that. The research is ongoing for a few years, but still in its infancy. We try to stay focused, to at least move forward to product, but you can imagine it's quite a big puzzle that we are trying to solve and with the help of some academic centers as well, who got involved. So we are working on exploring and developing the concept.
John Simboli:
34:30
If Pleco Therapeutics develops the way you hope it will, how much do you allow yourself to think about just how much of a change you could make for patients? Or is that something you think about later as you as you learn more, and you get further down the process?
Ivo Timmermans:
34:45
I think we are already thinking of what that will mean to patients. As we see it, we're developing a whole new field of science, And that sounds a bit exaggerated, but this really is something that only few have explored and have really looked into. And it allows generation of a whole portfolio of products that might help in diseases that are difficult to treat. For good reason, we start with orphan indications, so with diseases where there's limited potential for effective treatments. So we hope to see a big difference there. For a company, I could see that if you can extract metals and slow down the disease process, and for instance, in leukemia prevent relapses or delay them, then you make a few steps in the direction whereby you can start to see cancer as a chronic disease that can be controlled. And we saw the same in the early days with tuberculosis, later with HIV AIDS, these were considered mortal diseases. But they're now diseases that can be brought under control, and people live their lives. And they have have a reasonably normal life. And I think, with certain cancers, I'm hoping we can achieve the same. And, certainly, we know that these metals perpetuate diseases, because they're still the underlying cause of chromosome damage and resurfacing of disease processes. So if we can control that better, then our therapy can hopefully help in making small steps towards controlling the disease. And that is actually my great ambition. I would be very happy if at the end of the day, we could show that. And applicable to many cancers, and for many patients. That would be wonderful.
John Simboli:
36:47
As you think about where biopharma is headed, and who knows where that would be over the next few years, do you see a place for yourself in a particular area that you want to be in the forefront of?
Ivo Timmermans:
37:02
Well, I think the areas we're looking for, and they all relate to the role of metals in disease, the areas we're looking for is oncology, neurology, there's some cardiovascular diseases, that's also known. So I would say, we try to promote the concept and find out more about the role of metals. And I think if that is more on the radar screen of large pharma companies, they might also take that into consideration when they develop novel drugs. And so I only see us as a sort of pioneer company who develop something which is a bit new, a bit strange, a bit out of the blue, but might be very useful for future companies. Particularly our preclinical models that we have set up and that we've now established, I think they might be quite useful to test future drugs, as well, to see how these drugs function in a contaminated animal model. So I see us as a sort of company that hopes to facilitate the future drug development. It's a big adventure. A very nice journey.
John Simboli:
38:22
Thanks for speaking with me today. Ivo.
Ivo Timmermans:
38:24
Thanks, John. It was pleasure to be invited as a guest. I enjoyed the conversation; thank you very much.