Philipp Spycher, co-founder and CEO of Araris Biotech, shares his thoughts with BioBoss host John Simboli about leadership in biopharma and how Araris is working to develop a linker technology for antibody-drug conjugates that enables attachment of any payload to ‘off the shelf’ antibodies without the need of prior antibody engineering.
Philipp Spycher, co-founder and CEO of Araris Biotech, shares his thoughts with BioBoss host John Simboli about leadership in biopharma and how Araris is working to develop a linker technology for antibody-drug conjugates that enables attachment of any payload to ‘off the shelf’ antibodies without the need of prior antibody engineering.
Today I'm speaking with Philipp Spycher, co-founder and CEO of Araris Biotech, headquartered in Zurich. Welcome to BioBoss, Philipp.
Philipp Spycher:Thank you very much, John. It's a pleasure to meet you and, about the discussion, very much looking forward to it.
John Simboli:How did you find yourself in this role as co-founder and CEO at Araris?
Philipp Spycher:I always considered this opportunity to sort of being a co-founder of a company and doing things for the greater good. I was always fascinated by that idea. And even actually, when I started, as a postdoc in the lab, my professor, I told him that if there's a chance to incorporate the company and build up something new and exciting, then I will definitely take this opportunity and build a company. But then when I started in 2014, there was nothing to build the company from. It didn't have any IP, and so on. I actually started as a postdoc, and then I brought in my own ideas during that time, which actually didn't work out so well. But when we started to combine the ideas we made this very surprising finding, actually, that we could directly modify antibodies, which then enabled us to incorporate, or first of all, file IP, and then incorporate the company. So we really had something at hand, which enabled us to build something and then we also, in parallel, reached out to investors and also pharmaceutical companies to probe their interest. And we saw a significant interest back then in 2017-2018. And so that's how it came all along. So it was pure serendipity always, but always having in mind that if there's a chance, I would do it
John Simboli:Had you considered taking this idea and approaching an established biopharma company and saying, I'd like to bring this idea in house, I like this idea to be a development program within this company? As opposed to the arduous path of starting a company from from scratch.
Philipp Spycher:It's a good question. We talked to really a lot of companies. And back then when we started, the ADC space was not as hot as it is now, you know, many agencies failed. And many said, yes, it's interesting technology. And then it was all about credibility, because we just could show that we can manufacture these ADCs much simpler than anybody else. And so it was also regarded, I would say, that people just viewed it as a manufacturing improvement. And then, when we started the company, we developed the technology further, we also realized that it has significant advantages which we think others don't have, besides the manufacturing. This is the feedback we got initially, then we say, look, it's maybe also too early for us to further develop this as of now. And so we took the risk actually to start the company. And we were very fortunate also that we had good investors that believed in us. And I also managed to assemble a world-class team of co-founders. It's a lot of fun working together with the team. But also I guess, everyone tells you, as the CEO, you work a lot, obviously. But as long as it's fun, I think it's great.
John Simboli:How did it turn out to be similar to or different from how you pictured it being, that is, starting a
Philipp Spycher:I think when you're a first-time founder, you company? just see all the work that needs to be done. And I had expectations in that regard that it would be demanding on one hand, of course, and also that it would be giving me a lot of opportunity to build something great. I mean, this was awesome, for sure, my expectations. And worked with great people together. Also, this certainly was an expectation I had and building a great company, as well. We are, meanwhile, not the only ADC company in the field anymore. Back then we saw the competition, but now there are more ADC companies, which I think validates us that we are on a good track so that the the ADC is space has heated up, actually.
John Simboli:What were you hoping to achieve that could be done at Araris that could not be done at another company?
Philipp Spycher:I think my vision was always that we can develop something that is very exciting. And something that also has the potential to actually treat cancer patients and improve their lives significantly. And so what our motto or our vision is really that we aim to cure cancer. I know it's a big word, aim to cure cancer. Everybody says that they develop some sort of anti-cancer drugs. But I think what we have developed, I think its simplicity, how it enables us to assemble those molecules and to really efficiently transport these highly potent drugs to tumor cells. And with the vision that it's only delivered to this place very efficiently and also the release is working. I think that's great and I am very excited about it. I think that's also probably distinguishes ourselves from other companies that we have this beautiful technology at hand that we think enables us to tackle the current challenges in the ADC space. The vision of delivering this magic bullet that Paul Ehrlich had a hundred years ago that is really becoming true, that we can selectively deliver a therapeutic drug to a cancer cell when it's been cleaved, and the payload is released and kills the cell. So this is how we hope to know that we think we are differentiated from other companies, biotechs working in the industry.
John Simboli:I'm curious about how one goes from being really excited about a scientific idea, and really well-grounded, as you were, to that next step of saying, instead of going out and hiring a CEO, I'm going to do this. How did you come to that?
Philipp Spycher:It's a good question. Maybe just to give you a bit more background on that and led, ultimately to incorporate the company and help me to decide to go this way. Because I'd also talked to other people in the field, and people who have been really senior management in big corporate companies, and so on. So I talked to them, and some of them said they have friends that took the chance to incorporate the company. Not them, they didn't, but they have friends who did it. And they sort of told me that they regretted that they have never taken the courage to incorporate their own company. And they sort of seemed to regret it now, despite working in a big corporation, having all the benefits of working in a big, company versus a small biotech. Because when you're in a small biotech, you're always running behind the money. And when you're at big corporate, the money usually comes on its own. I think this sort of impressed me a lot that it seems building your own company from scratch and building co-founders, and going through good times and hard times. I think that's really what's fascinating me. Obviously, you also need investors and co-founders that believe in your role as a CEO. And I think in that regard, something that was, from the beginning, very clear, and it's great that there is definitely support, and I'm very happy and also excited about that. And I also feel very comfortable in this role and being a CEO. And I think I have also done very well in that regard, because I managed to raise significant amounts of rounds, first financing round and also establishing sort of evaluating deals with pharma, and so on and building the team further with world-class co-founders, and also a world-class Scientific Advisory Team and also in general building the company further. And of course, it's always about the team. That's really important as well, and I'm very fortunate to have a compelling team on my side that works day and night as well.
John Simboli:Do you remember what it was like when you were maybe eight or nine or 10, and you had an early image of what you want to be as a grown up? And for most of us that's trying to figure out what your parents thought you should do, right? But can you remember that? And can you remember, does that have anything to do with how your professional life is now?
Philipp Spycher:When I was a kid, and I eight or nine or at this age, I think I always had the feeling that I would . . . first of all, I was always fascinated by science. So that's the first point. And I always wanted to build things. I think I always wanted to know how things work, in general. So that's one aspect. And I was always about natural science as well. So this is also something that interested me really a lot, how things work. And I always wanted to build nano robots. So this was because when I was a teenager, and this age, there was really the big time of nanotechnology. Nanotechnology was how you cure cancer, how to build these tiny machines that then go selectively to the cancer cell and kill the cancer cell. Also several Nobel Prizes were also in this time, I think, given away for building instruments that were able to resolve the anatomy and structures of molecules. And also in terms of television, there were TV shows about nanotechnology. It was super fascinating. And also during high school, I remained interested in this nanotechnology and I actually eventually started nanotechnology because there was just a newly launched curriculum at the University of Basel, which is called nanotechnology. And I was really pleased to see resources that are different in order. It's not only about one part of science that will be about physics or chemistry, but it was about biology. It was about physics and chemistry, and I always liked all the sciences because I always thought for physics I'm probably not smart enough. But I always was fascinated by physics and I was fascinated by biology and chemistry and to build nano instruments. So I also asked the professor, look, I want to build nano robots. What direction would you recommend I go in? And he didn't really clearly state but for sure, he said it's good to have a general knowledge, be a generalist in everything. And then I eventually realized at the end of my study that it's a bit difficult to build nano robots, because the technology is not quite there yet. So I realized that there is another way to build a ltargeted delivery, which is through ADCs, actually, and this in the middle of my study for my doctoral degree, I realized that it's possible to hook up chemotherapeutic drugs to a cancer drug, which is close to a nano robot. And this is what I actually ended up in. It's still about targeted delivery, but maybe not through a nano robot as I ewished 30 years ago, but it's fine. So it's still about curing cancer. So it's good.
John Simboli:Would you say that your fascination, your pivot from the nano robot part to the ADC part, did that place you in the early stages of people looking at ADCs as a therapy, or has pretty well been established at that point?
Philipp Spycher:I mean, when you look back at the history of ADCs, it's an old concept, but it has just been very challenging to attach this, I would these chemotherapeutic drugs onto antibodies, because they have completely different molecule, chemical properties compared to an antibody. And people struggled a lot, how you attach the drug onto the payload, and I think there was just one being approved. And then it was withdrawn because of the side effect profile of this ADC. And it must be re-approved. So I was just at the very edge of this ADC technology, so I was just thinking, I don't know, two levels ahead already. Or I was already looking 50 years ahead of building nanotechnology based robots,
John Simboli:When you had that moment of enlightenment that you could approach antibody drug conjugates in a different way than had been before was that, as you remember, was that kind of like, oh, yeah, I think I'm gonna pursue that, or is that more in the quality of this is really interesting!
Philipp Spycher:First of all, we didn't believe that it would actually work because then we saw it first in all the measurements, we thought it would be an artifact. We broke, actually, a dogma, because I did the postdoc in the lab, where everybody said, look, when you use this approach, you need to modify the antibody. So you need to do some upfront modification on the antibody. So it was really a total surprise that we could actually efficiently conjugate the payload to an antibody. And then, then suddenly we just tried out and investigated it what actually happened. And then we started to realize, okay, so it works now. And then, as mentioned, we also applied for a founders fellowship. At the institute, when I did the postdoc, it just launched also in parallel a program which enabled me first of all to apply and to ask for money, so that I could go out to a market analysis, like talk to big pharma companies, and VCs and probe for their interest. And this program really enabled me to see, okay, there's interest from the market, and there's all the interest from the VC field to support the idea and the finding. And this actually led to the incorporation and further development of this discovery because it was not initially clear. In Switzerland, we have a very viable startup scene, you know, you go and pitch and there are investors and you get feedback. And there are even sort of big corporate CEOs present from pharma companies even or other smaller biotechs. I attended one of these pitches and was a finalist there and there was also one biotech CEO from another company, and he told me, it's really interesting. He told me, Look, it's very interesting what you do, but I think you're five years too late working on ADCs because now it's all about CAR-Ts. I was like okay. You get really mixed feedback, and then you just continue your journey against all expectations. And here we are. Five years later, everyone talks about ADCs and CAR-Ts,. mybe as well, of course, but it'svery hot obviously now. So it was it's very funny, actually, sometimes.
John Simboli:I guess everyone runs into it right? The variation on the, well, if this is such a good idea, why didn't somebody think of before? Or, you're too late to the party. You have to find a way to deal with that, right?
Philipp Spycher:You just keep talking to people. And you just believe in the idea. And I think that's very important. You just keep going, to the very last. And you just learn along the way; it's continuous interest. So while I just finished up this program, we were very lucky also, that we could do a proof of concept study with an external company, and we had really good data there as well, which then enabled us to secure financing. So the first financing round with a seed investor. So it's really step by step and but it's really continuous work, convincing.
John Simboli:When you were in the lab, and you realized that you had, I think you used the word broken a dogma, I can't remember the exact phrase, but what is that like? I mean, that probably doesn't happen to every scientist, that you turn the
Philipp Spycher:I think the classical or the conventional tables? reaction that you have is it must be an artifact, you know, because it's against the expectations that you have. They think, oh, it must be an artifact. And then it was actually not me but a PhD student who did the experiment. And the question is, maybe he did a mistake? Or where does it come from? It's always about the order, because it's something totally unexpected. And then you just do additional controls, and so on. And this is really a surprising finding. And, obviouysly, we involved the professor here. And then it was over. And he also didn't believe it initially. And then we just generated more data. And this is how it came about, actually. I think it's also important when you build something exciting that you don't think it's an error, you know, that you really go and have a dive here, see what's actually happened. It's not an artifact and so on. So it's the mistake, sometimes that brings you one step ahead.
John Simboli:What have you found about your management style as a CEO that works for you, that defines who you are? That makes makes Araris work?
Philipp Spycher:I really value people a lot for what they do, and also show them my appreciation for all their hard work, because I know everybody in the lab is actually is working really very hard to move this forward. Because ultimately, it's the team that actually moves the company forward. And I think that's really important that we show valuation of that. And also giving the people the freedom to work independently. Also, no micromanagement. I think I'm not that person that does micromanagement. We also involve people in how we decide so we really discuss, a lot, how we move forward. Not excessively, but it's really important that we involve people and also make decisions among each other so that it's carried mutually I think it's really important on in that regard. I always say work hard, play hard. I think that's also very important. And also that people are allowed to have a small fraction of the time also to pursue also their own ideas to some extent, I think that's also something that is important. Exploring the unexplored, I think that's also important.
John Simboli:How do you decide when to jump in and help on something and when to stay back?
Philipp Spycher:I trust people a lot. I think that's also very important, and also just that they can sort of fix their problems, because they're usually the experts on what they do they have a better understanding on that topic, and very detailed.
John Simboli:So when people say who is Araris? What do you like to say? How do you like to answer that?
Philipp Spycher:I tend to say that we are developing oncology drugs and that we are aiming to selectively deliver chemotherapeutic drugs to the cancer cell so that we can also have a better efficacy and lower side effects. Because what we do is to target the delivery, delivery of chemotherapeutic drugs and we just want to significantly improve on that while also improving on the side effects.
John Simboli:When you give the introduction you just gave to me, when people hear it the wrong way, what do they tend to get wrong? And then how do you help help them to get it right?
Philipp Spycher:People sometimes think of us, or investors think of us, that we may be a CRO, so a contract research organization. But we are actually not doing any CRO service so we are not a fee for service.And it's really important that we are a drug development company. So we have this link technology. And our vision is really that, based on this link technology, we are developing own ADC assets, which we want to bring into clinical development and really make a difference for patients. I think it's important, in that regard, to understand. And of course, we are remain very interested in providing access to our link technology. But we are not, as such, as mentioned the fee for service company. It's not something that many investors like. And also we think it makes sense to focus really on developing the assets and providing access to our technology through such a business model.
John Simboli:When you go into more detail, and you begin to talk about how ADCs used to be designed prior to your involvement, how ADCs were designed, how they were produced, how do you describe the way it used to be in the way you're doing now? What is the distinction?
Philipp Spycher:ADCs are very complex molecules, because you have the antibody, and you have the payload that you would like to deliver. And then you have to link it obviously in between. So you have actually three components that you need to optimize. And as you can understand the linker, it acts like a glue between the antibody and the payload. And when this glue sort of dissolves, while it is in blood, you lose the payload. And when you lose the payload, and because it's a very potent payload, it causes severe toxicity in the blood. So it kills the blood cells and also you lose efficacy. And that means that you have toxic side effects before you actually see the tumor being killed. So you're limited by toxicity. And we can beautifully address this challenge because with our technology, we can generate very stable molecules. So with this glue, so the linker, the thing between the antibody and the payload, it's very stable. So therefore, we don't lose it while it is in circulation. And we can therefore very efficiently transport the chemotherapeutic drug to the targeted site, and to selectively deliver it. And also we can assemble those molecules very efficiently. We can hook up or glue it together, let's put it that way, in just one step. And we think that's really very elegant as well, because it avoids manufacturing issues. So therefore, we can really address the two main challenges in the ADC space very beautifully, because we can generate very efficient ADCs that are very safe, and also can assemble those molecules very efficiently. So that's why we think we are really very well positioned in that regard.
John Simboli:How does the pipeline express your your vision for the company?
Philipp Spycher:We have one lead asset for a liquid tumor or hematology indication and also the second program for a heavy solid tumor indication. The vision is for the first program that we validate the linker technology. Because here we are developing an ADC based on a comparator ADC which is already FDA approved. So what we do is we take the same antibody and the same payload, but just exchange it with our linker because this linker that is used for this ADC that is FDA approved, we think it has drawbacks in terms of it cannot really unfold its full potential unfortunately. I mean, it works in the clinics, as mentioned, it's FDA approved; it shows a reasonable efficacy. However, the safety profile, and also the efficacy profile, it's really sort of limited for that ADC. And also it's only approved in a certain indication, but not in another indication. It was investigated in another indication, which is actually in indolent lymphoma or follicular lymphoma. However, it was not approved there, because it had too strong side effects, which we think is quite a pity for the patients because it actually worked really nicely in this indication.. It became sort of unbearable for those patients. So 85% of the people actually had to stop the treatment because of the side effects. And for the lead indication, we really envision that we can use the same as much antibody, same carrier and to same payload and just use our glue or our linker to make it much more stable. As I had mentioned before, to really address the shortcomings that is faced with this ADC this FDA approved so that we can treat even more patients with the current indication when it's approved and hopefully be much more efficacious and much more tolerable compared to the FDA approved ADC. But in addition, also go into an indication where the other one actually had failed. And then we can really pinpoint it down and say, look, the only difference between this FDA approved ADC and our ADC, it's just this tiny little piece, which is responsible for all the differences we see in terms of efficacy, and also in terms of tolerability. And we think this would be a very huge case, because the same technology that is used for this approved ADC is also being used for three other FDA approved ADCs because it's considered as the gold standard in the ADC space as of now. We think we can potentially, this is also my vision, that we can potentially replace this technology with our link technology. When you look also in the space people, people tend to change more than one parameter. So it's usually the linker and the payload. So it's always difficult to sort of know where the difference actually comes from. And in our case, we just want to change one parameter and to really validate the link technology. Because this is what what we see, what what people generally believe that in the ADC space, when you attach the payload in a very well defined manner that you can improve on the shortcomings of the ADC so much that you can go into an indication when it has not been possible. You know, just make the cake bigger. But, actually, no one has shown it so far, at least as we see it. I mean, pre-clinically, there are some data that indicates this, but it has not been really validated meaningfully in clinical development. And we really want to be the first ones to show that we can say look, site specific payload attachments, so that we can really control the drug's attachment on the antibody, it makes, it makes a huge difference.
John Simboli:If Araris develops the way you hope it develops, how much effect could that have for patients?
Philipp Spycher:We hope that they can really make a significant contribution to patients. Because when you look at current ADCs, and particularly the ones we're comparing ourselves with, I mean, it works. But the the pity is really that people have to stop treatment within few months, because they cannot bear the side effects anymore, and also become resistant, and, we think, become resistant to the treatment. Because we think it's also due to it loses the payload, and then people are to some extent constantly exposed to the payload in the blood. And then the cancer cell develops natural resistance, we understand, against this payload. And we think when we can avoid that, and if we can more selectively deliver it, we can address that shortcoming. And therefore, we think we can hopefully treat patients much longer and then we can say look, we can cure people allow much longer than was possible before. And also particularly, in the other indication, it has been not possible to go and we can also show because in this indication, you need to have a high therapeutic index. So it means you need to have good tolerability and also have good efficacy. And that's why we think it all works out. It could be a game changer in the ADC space. I know it's a big word, but, you know, we always aim for the stars.
John Simboli:What is it about the mechanism of action that Araris developing that is so exciting to you? And, you know, when you tell other people about they get excited?
Philipp Spycher:I think what is really unique about our technology, and also the mode of action, it's really how we assemble it. So first of all, we use native antibodies, we don't need to engineer the antibodies. And, that's one aspect that we're definitely very excited about. And also the fact that we use the peptides, as a linker. Peptides are built from amino acids, and amino acids, it's the natural building block of every protein. Every protein is built from amino acids. And that's why also we're really very fascinated by the technology because we use peptides as linkers. So it means that when the human body is familiar, to some extent with with peptides, because we use very short peptides. So that's why we also don't think it could be a problem in terms of immunogenicity. And therefore, it's stable because peptides are very stable, which means that they're stable in circulation and also to certain enzymes, not too much exposed and so on. So that's one mode of action, you know, being a peptide and therefore the inherent stability of a peptide. And on the other hand, also because it's a peptide, it can also be cleaved. Once it's has reached its targeted site, it can also be cleaved very easily. When the ADC has been degraded and ripped apart by enzymes, the linker then becomes available or exposed, let's put it that way, then the body can just use its natural toolbox to cleave the linker. And therefore to release the payload. And also when we look at actually what is generated, or metabolized in the end from, from a peptide, it's, again, the small amino acids, to which the human body is very familiar. to, We think this is in stark contrast to other linkers in the ADC space, because they always use polymeric based linkers, which are sort of artificial, it's not known to the human body, you've changed the way it's metabolized, which could potentially be monogenic, or, in particular, when you think of when and ADC enters the cell and it kills the cell, then the question comes. So the cell is in very stressful state. And then it also generates certain cytokines and so on, which may be a problem for the immune system. And particularly because the ADC typically not only goes to the cancer cell, but also the healthy cell, and you tend to kill the healthy cell as well. What comes out from this healthy cell, it's the metabolites. And in their case, it's an unnatural substrate for the human body, which may be monogenic, it may also cause additional side effects. And in our case, we think this is really unique to our linker technology, that it's actually really biocompatible in that regard that we chop the linker off in single amino acids, and what remains is just the toxic payload and single amino acids. We also think it could explain this remarkable improvement in tolerability we have seen in multiple different animal species. We have really shown in rats, and now in monkeys that we can substantially improve the therapeutic index compared to others. And we think this could lastly, also be because we have such an excellent biocompatibility of our linker, so that it should not cause any inflammation, because as mentioned, it's just amino acids. Then I did the master's degree, you know, I studied biomedical engineering, and it was always about implants, you know, the question is, when you implant something into the human body, it should become or should be biocompatible. Because when it's not biocompatible the body will actually refuse it and generate inflammation. It's the conventional classical case is hip implants. That's why everybody uses titanium, not just any other material, because it has such an excellent biocompatibility. Coming from this angle, I think, why should this not only be true for implants, but also for linkers? Because it's also needs to be biocompatible. I think particularly when you have cancer and everything is anyway in in an alert situation, where everything is out of balance, and then you come with something that is not biocompatible, it may cause things to get even more out of balance, causing even more side effects.
John Simboli:You know, as you were speaking there, I actually began to picture that pivot from your earlier focus on nanotechnology and the robots to where you ended up. There's an engineering aspect to the elegance of your biological approach, isn't there? It's interesting.
Philipp Spycher:Absolutely. It's an engineering approach. And this is why I say I'm very fortunate to have studied something which is about biology and chemistry and physics. Of course, I'm not an expert in all this space, which sometimes is also limiting. But I think overall, I think it's very helpful to understand all the components growth of an ADC, the biology, the antibody, the chemistry from the linker payload, and also the toxicity from the biology. I'm not an expert, I have to ask somebody, and but that's why it's important to also have a heterogeneous team, particularly for ADCs because it touches all the topics. We have really a lot of chemists in house, but also people who have more of a biology background, I think it's really important to be successful in the ADC space. And and I think that's also something I'm proud of, because this engineering aspect, I think it's very beautiful for our technology, this mode of action. It's stable, but on the other hand, it can also be degraded. Because sometimes when it's too stable, you have problems in efficacy because the payload is not properly released. And also the bones that we use to attach the linker on the antibody. It's an enzyme that we use, it's a transglutaminase. And it's a glutaminase and the bond that is created, it's actually a natural bond. And the human is capable to deal with it. I1t's really exciting for me and I think also for the team. It's this consistency. We see a consistent improvement inndices for all the ADCs we have looked at so far. So we always include a comparator so that they know where the difference comes from. So we use always FDA approved ADCs to compare ourselves and we just exchange with our linker so that we can really pinpoint and it's really the linker that makes a difference. This is something very rewarding that we see this consistency.
John Simboli:Thanks for speaking with me today. Philipp.
Philipp Spycher:Thank you very much, John. It was really a pleasure to speaking with you and thank you very much.