Transcript
Fabio:
Welcome everyone. I’m here today with Mark Bonyhadi. Mark, welcome. So Mark used to be Vice President Research at Juno. He’s now on the board of TC Biopharma, on the board of Integra Therapeutics, Scientific Advisor at Akron Bio, and also Senior Advisor at Qiming Venture Partners. Mark. It’s a pleasure to have you here today.
Mark Bonyhadi:
Thank you so much. Appreciate it.
Fabio:
So Mark, we’ve seen so many, like more and more cell and gene therapy products being approved recently and the potential of these cell and gene therapy products is impressive. But at the same time, turning new research into medicinal product is a long and difficult journey. What do you think gets in the way and why? What makes the process so challenging and difficult?
Mark Bonyhadi:
Yeah, well, there are a variety of things. And I would just start with the basic pieces. Once an idea is conceived in the lab, there’s a proof of principle in vitro or even in vivo. All the little pieces, the check boxes that you need to put in place to move it, one, into the clinic, two, into later phase trials, and three, into a viable commercial product. There’s quite a few items in those check boxes that need to be filled. I’ll give you just one example, the CAR-T space. You know, we had our first approval a few years back, both Novartis, Kite, Juno, now BMS, and Gilead and all those guys got these approved, but the first patent came out in 1988, the first paper in 1989 by ZELIG ESHHAR, that’s, you know, a good 30 years. It’s a, for most cell and gene therapy products, now the tools and technologies are so much better. And the conception part proof of concept is okay, but you need to build in all the pieces needed for supply chain, regulatory compliance, safety, all the analytics that you’re gonna do to meet the regulatory requirements. And then the bottom line too at the end is cost of goods. Can you do it in a commercially viable way? Otherwise it becomes very boutique. So There’s a lot of different factors in there.
Fabio:
Thank you. Yeah, and now I’m interested as you’ve seen it also on the other side of the table as a former operating partner and now in your current role as Senior Advisor at Qiming Venture Partners. How can you successfully combine this long translational process that you described from research to clinical and then market for a VC-backed biotech company.
Mark Bonyhadi:
Yeah, I mean, that way it kind of, it varies. Depends on, you know, the VC focus. There’s some people that are focused like on tech, develop things. There’s a whole variety of investment opportunities. When you move to the biotech, it’s also becoming more complex because that includes both biologics, you know, gene therapy, cell therapy. It includes AI-based, you know, monitoring and… digital monitoring, all these new technologies. So it really is a large pool of opportunities. In spaces like cell and gene therapy in particular, we have a long history of companies being developed in a smaller number of successes. So I guess the underlying, the three, two or three principles that are really underlying in any VC’s mind when they look at a concept, whether it’s a seed stage or a later stage, is the concept, is the concept, is a good proof of concept for the application? Does it work in small models, larger models? Is the team that’s going to try to put this together, are they qualified, are they good for that stage of the development? That’s, I can tell you that almost every VC will look at the team. If the team’s not good… the people who are trying to implement it, whether it’s a CEO, CSO, regulatory people, those people, you don’t wanna learn on the fly on all these things because that takes time. But again, in a new space like cell and gene therapy, there are not that many veterans that know all these pieces. So that’s very complicated. The other piece is what’s the market, what’s the indication in the competition? Can you meet a timeline so you won’t be out competed? And I guess the last piece is, you know, what’s the real commercial opportunity there as well.
Fabio:
Thank you. Thank you. And like you mentioned Juno at the beginning, so I remember you helped launch Juno in 2013. And what do you think is available to cell-therapy companies today that wasn’t available basically 10 years ago?
Mark Bonyhadi:
Yeah, so two points. I want to point out the first one that Juno, Kite, Novartis were lucky that what they started to move forward was a therapy that already demonstrated strong proof of concept in the clinic in the UPenn trials with Carl Juno and CLL patients, those earliest patients. So that was a luxury that almost no one else has. Oh, I’ve got something that works. Now I’m going to commercialize it. I just have to not screw it up too much and get there in time. But all the other, in terms of the technology, the tools that are available, they’re really amazing. I’ll give you one example, the use of AI machine learning in data analysis for large bits of data to be able to actually get much, much more predictive than we were, to be able to segregate targeted clinical groups into different groups to understand will they respond? Are we building this right? So that’s in the clinical response, but also in the design, protein engineering now, and other things like that, or spatial organization for identifying targets, using the new tools for better imaging, mapping, associating with clinical outcome or clinical state or previous history, those tools are widely available, and I think many of the successful companies these days are building a big… he said that AI and the technology for data acquisition, whether it’s gene sequencing, whether it’s epigenetic information or spatial understandings of interactions of molecules, you know, down to the molecular scale, those tools were not available and now they are there. There’s still a lot to be refined and integrated, but those will make a quantum leap and… in how we develop drugs in real time in the near future.
Fabio:
Yeah, that’s extremely interesting. I’m looking forward to 10 years from now and the technology that we’re going to see for like to manufacture cell and gene therapy products. So, back to Juno for a moment. So Juno was acquired by Celgene in 2018 for approximately $9 billion. Can you tell us a bit more about the story behind that what led to the, basically to its success?
Mark Bonyhadi:
Yeah, I think, again, you know, I harken back the fact that there were three patients in this early CLL study at the end of 2010 or 11. I think, yeah, one of those two, where the data looked so strong and all of a sudden a lot of money was getting thrown at this technology because it was working. And so Juno was a fortunate benefactor in that as it spun out of the Fred Hutch and brought in some… folks from Children’s Hospital and the folks from Memorial Sloan Kettering, which is pretty unique to bring in what I call some competing groups to work together and consolidate those resources. That really, I think, helped accelerate, you know, bringing more tools and more good minds together. Plus the fact that the story was so intriguing that it was much easier, I think, to raise money. I mean… If you look today, today’s market is much, much more difficult, but at that point, this was a big story and so it was easy to raise money and the trick is how do you make sure you don’t waste it. But then it’s also building the team and these therapies have multiple components. These were autologous, every product’s unique, you’ve got to gene modify them so you have to build vectors, you have to build all the analytics, you have the whole process development expansion piece that takes a while to go from an academic setting to a commercially viable, GMP, you know, approvable drug kind of setting. So those were the challenges. And I believe that, you know, what we saw is between like Kite,Novartis, Juno, and a few of the others, they really built a large army of people who all of a sudden were learning the CMC skills, the regulatory requirements, the roadblocks. You know, all the nuances of manufacturing, supply chain, all this. So, you know, it was like the first class 101 in successful gene therapy for CAR T. And now a lot of those players have disseminated out to other places, are educating other folks in getting new education in from, as you said, that adoption of new technologies that are evolving. So, you know, Juno, Kite, and Novartis were all lucky in terms that this was clinically almost ready, but there was a lot of learnings that people came in with expertise for manufacturing, but it wasn’t a gene modified cell therapy manufacturing of commercial scale, so there was a long learning curve. And I could probably say that all these products could have been out there a year or two earlier if everyone had more education, didn’t have so many roadblocks and surprises because it was their first foray into manufacturing a living cell product.
Fabio:
There’s been a lot of experience, lots of good people, like good experts coming together even from competing organizations. That’s probably been the success and probably a bit of let’s say luck into being together at the same time.
Mark Bonyhadi:
There was luck, but the other thing I have to say, and I always forget this because I’m a scientist at heart, but we had Michele Sadelain, Isabel Riviera, Renier Brentjens, we had Mike Jensen, Stan Riddell, and Phil Greenberg from the Hutch. So we had a stellar, stellar team. But then we got in, I think, when we brought in Hans Bishop to kind of… start the flow and brought in a few key players. Like I said, when we started on October 21st or 22nd of 2013, there were like eight of us or nine of us, and built it from there. And it was all whiteboard exercise then. The key was, how do we get in the key people that can lead these separate pushes? And that was the fun and exciting part. And unlike today, we had the luxury of having pretty good financing and because of guys like Steve Harr and Christian Hordo and Hans Bishop and all these guys we got a very nice good relationship early in financing through Celgene which really opened the doors of possibilities for us and I don’t think that luxury is around for that many people today and so it’s forcing people to be more streamlined, more narrow-focused and really precise on what they’re going to do they can’t they can’t wander too much outside those side bars or the safety bars there, You don’t have that luxury
Fabio:
Well, that’s unfortunate. Hopefully, it will change again, but it happens. Different stages of innovation, I guess. So you are certainly very passionate about science. And what do you think will be the next big thing in the cell and gene therapy industry?
Mark Bonyhadi:
So, I mean, like the next big thing, like next year or five years or 10 years, if we’re looking at the 10 years, which you’ve already mentioned
Fabio:
Yeah.
Mark Bonyhadi:
I had my eyes opened at the end of my tenure at Juno. Sorry, I was going through all my biotech companies there, the self-serving companies there. At Juno was the application of AI machine learning to the data sets we have for… delivering cell gene therapy products to patients in the oncology space, but I’m sure this plays in the autoimmune, neurodegenerative spaces, you know, many of these spaces. And what it showed me is that we can be much more guided, educated, and precise on how we focus our efforts. When you combine that data acquisition massaging to pull out the diamonds in the rough, you combine it with some of the more advanced tools. For example, everyone does flow cytometry, everyone does gene sequencing, and more recently, which I think is actually kind of that next, it’s going to like a new dimension of analysis, is the epigenetic information. I have this concept where like the DNA in every cell, except for some T and B cells that mix up their genes. The DNA is the same in every cell. Why are they all different? Why is the hair cell or a brain cell or whatever it is? And it’s about the operating system and the epigenetics, the modeling of the chromatin. So it says what can or can’t be expressed, what is being expressed or poised to be expressed. And it’s like on your computer. You can have a bunch of code in there and you can write over it and all that. But when you get upgrades, you get a new operating system, right? improves the performance, it allows you to do more applications. And I kind of look at our cellular DNA that way. And so there are companies like Tune Therapeutics here in Seattle and a few others that are looking at epigenetic editing, modifying not the DNA, but the operating system to regulate genes that may be associated with diseases. And as soon as you can start combining the gene replacement or gene editing or gene writing with epigenetic editing or modifying the operating system, now you have multiple toggles in a single delivered therapy that allow you to very fine tune things and understand the control. And so that’s one space. The other space is really all the, is the space of like protein engineering and 3D spatial understanding of formation of complexes, whether they’re signaling complexes or… you know, whatever it is that are associated with disease so that you can find new targets for intervention or new protein designs that, you know, escape or reduce immunogenicity, they bind with a desired affinity, they’re just better home, they’re like evolution in, you know, mini evolution, rapidly controlled mini evolution so you can get to these novel constructs quickly and test them quickly. Those are the areas that excite me the most. The novel protein design and AI applications there, machine learning, as well as the cell and gene therapy, particularly combining things like gene writing, editing, and epigenetic modification. To me, that’s like,
Fabio:
impressive.
Mark Bonyhadi:
I can’t wait to see it.
Fabio:
Well, yeah, it would be great, the epigenetic itself, like then if we apply and you combine, as you said, to gene editing, it would be huge. And now, last question I need to ask. As you know, we hope to be inspiring, and I’m sure we will inspire young researchers. So what would be your advice to a young researcher who will be listening to your video interview and they would like to start the journey from turning their research into new medicinal products. What would be your advice?
Mark Bonyhadi:
This is the easiest question because I spend, I’d say, about half my time now is mentoring people right out of college or out of grad school or out of post-docs to help guide them and try to put them in a network of people who can answer those questions with other opinions than my own. So mine’s really simple. And in a way, it reflects my story because I was kind of a lost. I didn’t start grad school until I was 32. something like that, 31, 32.
Mark Bonyhadi:
So I couldn’t figure it out, but what I found was something I was interested in. So I was interested in science, I knew that. So I went to grad school at Berkeley, and I just kind of fell in love with these places where these puzzles and questions arose, and I wanted to answer them. And so the advice is like always do something that you find intellectually challenging, interesting, that if the times are bad, at least you’re doing something that you think about that makes you think, that makes you try to be creative in finding solutions. When times are good, then it’s the best of both worlds. But the other piece is for young folks, some people will go right into… you know, big companies, some people go to startups, they don’t know where to go. My advice to them is always go to a place where you can do something that is in or adjacent to the space you’re really interested in. You will learn more about that space and what tools are being applied in this organization to solve those problems and always learn from these people and maintain those networks, always. The network is probably one of the most important things because that’s how people end up coming together to build solutions. And the other piece is recognize that it takes time to build your career. Don’t try to skip ahead too fast. I mean, you can if you’re successful. Kudos to you. Most people I know that do that, on the science side of things, run into some issues. It’s good to build your resume, your knowledge set, the breadth of what you’re doing and know where to go to other people to get answers you may not have. So those, you could do those. So any job you would take, try to look at who you’re gonna be working with. You don’t wanna be cubby holed so much that you’re not gonna get a chance to see the rest because it’s by building that communal knowledge, that experience that you can start to really build out your ideas so that you learn the basics. You learn what’s being done in the trenches. You go up a level, you see that and then you continue that overview. And it’s when you get further up and know all those pieces, you can be so much more effective. Maybe you’re not doing a pipette yourself, but you know exactly what they’re doing and you know, it’s like building a symphony, right? You’re bringing in the horns, you’re bringing in the strings, the percussion. And if you enjoy building something, be patient, it takes time. The CAR-T took 30 years, hopefully not that long, but for… you know, game changing things, it takes a while. So learn, be with good people, be patient. There’s nothing wrong with being at a low level and working your way slowly up. I admire people who do that because over time they move towards what they want to do, what interests them, and they accrue so much value that eventually you will be rewarded for that patience and vision and ability to bring a lot of things together. You know, I just like last night we had friends over my wife said, Oh, you know, Mark was part of these companies that babies, you know, these CAR-T cells, all this stuff, you know, his work and I said, I, I did the smallest little pieces and it’s like cogs in a big wheel to make this happen. It takes community, but it’s nice to be able to feel like, oh my, you know, my spouse is saying, oh, he did something important. So from the personal point of view, even if you’re the person working in the supply center of a company, just shipping and delivering, if you’re part of that cog in that wheel, you’re doing something important.
Fabio:
That’s great. That’s true. Amen to that. And thank you Mark. Thank you so much. It’s been a pleasure to have you here. Bye bye.
Mark Bonyhadi:
Well, thank you. Have a lovely day. Ciao
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