First in Human Episode #48 featuring Jonathan Thon

Jonathan Thon

Embark on a fascinating exploration of biotech entrepreneurship, guided by an expert who’s been in the trenches: Jonathan Thon, CEO and founder of STRM.BIO. We’ll give you an insider’s view of his journey from academia to the cutting edge of biotech, unveiling his trailblazing work on platelet production and the transformative potential of extracellular vesicles in gene therapy.

Rich McCormick: Hi, I’m Rich McCormick, Executive Vice President of Clinical Strategy here at Vial. Today, I have the pleasure of welcoming CEO and Founder of STRM.BIO, Jonathan Thon, to our First in Human podcast. Hi ,Jonathan. Would you mind telling us a little bit about yourself? 

Jonathan Thon: Happy to. I’m Jonathan. I’m the CEO and founder of STRM.BIO, as you’ve said. I was an academic scientist before becoming an entrepreneur. I was a professor at Harvard Medical School for a number of years, founded my first biotech company out of my academic lab and joined that company as its CEO and Chief Scientific Officer. I ran that company for almost a decade. about three years ago, I stepped away from that company and found STRM, which is my second biotech company. 

Rich McCormick: Can you tell us a little more about your journey from being a professor, and lecturer at Harvard Medical School to becoming an accomplished biotech entrepreneur? As you mentioned in your intro, it would be interesting to hear about your transition from CEO and CSO at Platelet Biosciences.

Jonathan Thon: The story really begins with my PhD work at UBC. I’m Canadian. University of British Columbia is a Canadian University I did my graduate school studies at. During grad school, I was working with Dana Devine, the Chief Medical Officer for Canadian Blood Services. 

Now, Dana was studying what was called the platelet storage lesion, or this characteristic of blood platelets to go bad after their short period of time in storage. Really, three days. Platelets are critically important. They’re the Bandaids of the bloodstream. I was tasked with trying to understand how to expand the lifespan of the platelet unit beyond three, four days.

We did a lot of tremendous work in that lab. But, it became obvious to me the solution wasn’t to extend lifespan by a day or two. The solution here was to disconnect the product from the donor, and make human platelets. It was with that idea that I came to Harvard. Initially, as a postdoc, and developed a microfluidic device to make platelets. This was one of the first self therapies being created at the time. During the course of that work, I was promoted to a professor at the University.

The work advanced to a point in my academic lab where the next steps were ones that required a little bit more infrastructure, and more of a commercial focus. So, scale up. Release a product. Regulatory process. Things that the university, or the academic lab really wasn’t set up to do, or do most effectively. 

I didn’t go into my academic career thinking I was going to become a CEO. Quite the opposite. I had never taken a business course up until [laughs] that point. But, it was also obvious to me at that point the technology we were building, a cell therapy, was way too early to license to any company. 

Quite frankly, the conversations I was having with investors at the time were ones around whether this was a medical device or drug small molecule. I told them it was neither one of those things. I was being told that if it was neither one of those things, it wasn’t a thing. And I would reply, “No [laughs] it is a thing. It’s just not one of those things.”

So, certainly, large companies, pharma companies weren’t in a position to in-license this technology. Staying at Harvard and continuing this would have meant the next 30 to 40 years of my academic career to do what felt to me, we could do over three to five years. But, in order to do that, I had to create a company of my own. 

Platelet ended up being an experiment in creating a vehicle to translate some of these ideas, and discoveries into the market. Everything else that followed was a very steep learning curve.

Rich McCormick: Your work has involved translating scientific advances into preclinical in clinical stage programs. Can you share an example of a particularly challenging scientific breakthrough that you’ve worked on, and how it eventually made its way into practical applications? 

Jonathan Thon: Triggering platelet production was that. In the academic lab at my university, we had discovered a way of exposing this parent cell to stresses that would trigger new platelets for production. This was a microfluidic system we were building it on, it was roughly the shape of a business card. The channels beneath that business card were a lot smaller still and, initially, was a two-dimensional device I had to convert into a three-dimensional device to increase the surface area, to increase the scale.

When we converted to a three-dimensional device, we also had to tackle challenges of even distribution of cells and flow across the surface area per channel. As we started parallelizing channels, the same thing across multiple channels, so we took up as much real estate as possible within that business card sized space.

We began stacking business cards, so to speak. And had to deal with manifolding inputs, and collapsing output challenges so we could flow through a single tube into a larger device, collect the product and pull that all back into a single output flow. In the process of doing that, we discovered media is probably the single most expensive component to any subculture process.

We were wasting a lot of it through single profusion of media through our device. We had to develop technologies, and strategies to [00:05:00] recirculate media. As devices got larger, we recognized it was too much work for one or two PhD-level scientists to be running over the span of one to two days. Quite frankly, that was not a scalable solution. [laughs] So, we had to automate the process. We had to miniaturize the footprints as well, so we could fit more devices into a smaller surface area. Had to adapt the manufacturing so we could move from what were initially machined devices, which were easy to iterate on, but expensive per device to micro injection molded systems which were a lot more expensive up front, but became pennies on the dollar when you’re manufacturing thousands of these devices at a go.

And then, we refined the operating conditions to optimize efficiency and yield. [Laughs] As I respond to your question, I recognize, in retrospect, we probably did a lot of work [laughs], but all of those things were important in scaling up what was a promising initial technology but turning it into a practical application.

Rich McCormick: That’s great. So a notable achievement as you mentioned is the production of functional human platelets from stem cells. You talk a lot about the discovery. How do you envision this breakthrough impacting the medical field in the future?

Jonathan Thon: Platelets are necessary any time anyone goes under the knife requiring large quantities of blood. If they’re in surgery, chemotherapy, receiving cancer treatment, childbirth, accidents, war. There were tremendous implications to platelet availability. The challenge was if you’re in the civilian environment, you’ve got huge shortages on long weekends, specific holidays, particularly warm or cold days where donors don’t go out to donate blood, because the entire system is dependent on volunteer donors.

What we discovered, as well, as we were building the company, is if you’re thinking about more international military systems, the movement of blood products, and specifically the movement of platelets telegraphs military engagements. Countries watch for this. It telegraphs where something’s going to happen. That’s meaningful. Because there’s not enough storage time in that product to bank it in advance of an incursion, or a defensive position.

This is a tremendously [laughs] important product with tremendous implications both in civilian and military applications. The initial idea, the initial foundation of Platelet, was based around producing these platelets and making them available to solve those challenges.

One of the interesting things I was also able to inject into the company, I think it’s very rare, especially for an early technology like this one, anyone gets an opportunity to introduce a second idea into a company. But I was fortunate enough to get a second idea into the company before I left, and turned the leadership over to who followed me at Platelet, while I went on to found STRM. 

This second idea was around cancer, and oncological applications. Cancer cells will actually coat themselves in platelets to hide from the immune system. They use that coating of platelets to metastasize inside the body.

The idea went, “If we could load platelets with anti-cancer drugs, we could also leverage that innate biology in that direct contact of platelets with cancer cells to help deliver anti-cancer agents and also prevent metastasis and kill cancer cells, before they took hold.

Rich McCormick: So at STRM.BIO you’re leveraging extracellular vesicles, or EVs to deliver gene therapy. Could you explain how this approach differs from traditional gene therapy methods, and what advantages it offers?

Jonathan Thon: Definitely. For starters, the vesicles we’re making, they’re cell derived vesicles. The vesicles we’re making are targeted and bypass the liver in vivo. Now, this is a big fucking deal. [laughs] I say that seriously because when we talk about the state-of-the-arts, viruses, lipid nanoparticles, when we talk about targeted, what we mean to say is that 90, 95% of the product ends up in the liver, and maybe 2% ends up in the target of interest.

What we have got here at STRM is a delivery platform that bypasses the liver in its entirety. That has huge implications in safety and dose. Now, if that’s the primary differentiator, the second differentiator here is these vesicles are quite a bit larger. They’re as large as the largest viruses. What that means practically for us is that they’ve got a large carrying capacity. We can fit bigger cargo in. We have successfully put in DNA, RNA, RNP so CRISPR-Cas9 complexes. We’ve been able to multiplex multiple different modalities, so the asset hits the same vesicles.

This is important because editors like prime dual flap editors, they’re getting larger and they’re not fitting into conventional delivery platforms. As the field starts moving away from just single-based permutation defects into more complex genetic diseases, we’re going to need to multiplex different kinds of cargo into the same vesicle to go after those more complex diseases. In order to do that, you need to be able to package them into a delivery platform.

The third sort of interesting component to this, as well, which we [00:10:00] found, is that in addition to controlling how many vesicles we inject per animal, per person, which is the conventional definition of dose, we can also modulate how many copies of cargo we put per vesicle, which is a really interesting independent lever that can help, modulate dosing. 

You can imagine scenarios where if you’re delivering an editor, you may not want a lot of copies of that editor per vesicle. But, you may want a lot of vesicles to blanket canvas a number of cells. Whereas, if you’re delivering a DNA or a messenger RNA for multi protein expression, you may want a tremendous amount of cargo per vesicle so that you increase as much as possible the amount of protein that’s being expressed on delivery. It is a really interesting lever that we can play with.

The third point is these vesicles are innately immune privileged. Which means that practically, we can repeat dose with them. Our field has for the longest time talked about one-and-done therapies for gene therapy. But, one-and-done practically is a tail wagging dog. We’re talking about one-and-done therapies because we can’t come in with a second dose, or a third dose. But if we could, and we can, this opens up the landscape in terms of the diseases you can go after, which is pretty much everything else, and the approaches you can take to go after those diseases.

There is one more point I wanted to make here. And I think this is tremendously exciting. It requires an understanding of how the gene therapy market has developed to date. One of the most exciting pieces of the platform we’re building is the breakthrough in the simplicity, versatility, and scalability of the manufacturing platform itself. And the implications that has on cogs. 

I’m hopeful that we can talk a little bit more about that in some of the next questions, because what we can do with our manufacturing platform is produce unloaded vesicles as a single off-the-shelf banked product. Because the loading of our vesicles happens exogenously, we can have a single common bank for multiple drug products. You can use the same product from one clinical application to another, and keep the same drug master file.

That is really exciting. It means preclinical, clinical data from one study can be repurposed for a different disease. You only need to update the clinical protocol as you move from one clinical study to a different clinical study. You’re able to keep the cost development low. 

What I mentioned about understanding of the nuance in the field is investors, as they think about selling gene therapy, they’re primarily concerned with this idea of cell and gene therapy companies require approaches costing huge amounts of money, huge amounts of investments in preclinical studies before a company can hit its clinical proof-of-concept milestones.

It’s been a gating issue for our space. What we’ve got here is a platform with the potential to limit the validation of cell and gene therapies to tox and efficiency of cargo independent from the delivery platform itself. That has the capacity of massively reducing the cost of the development for partners. 

I’m going to end this with just one more point, and going to quote Peter Marks, who’s the director of the Center for Biologics Evaluations Research at the FDA. He gave a presentation at the Meeting On The Mesa this last year. He said, “If we could get this paradigm to work, rather than having the manufacturer go back and do all of the preclinical toxicology, and give us all the manufacturing information each time they submit something, they would just cross-reference. And this would allow us to focus on innovation that’s going to benefit people.”

He said, “We’d start by allowing an individual company to leverage the information from one application to another, and then if that’s working well, we can consider expanding that concept further.” And I think that’s really at the heart of what we’re trying to build at STRM.

Rich McCormick: That’s really exciting. I truly appreciate that level of insight. Obviously, you mentioned being at a conference, recently. I know you do a fair amount of speaking at both conferences and meetings worldwide, could you share a piece of advice that you would emphasize when speaking with an aspiring scientist or entrepreneur in biotech?

Jonathan Thon: Do it. [laughs] Maybe three things I can share. The first is. Do it. There are all of the reasons in the world everyone will highlight regularly for why something shouldn’t exist, or couldn’t work. But, if you can see a path whereby it can, you should do it. 

For all of the reasons everyone keeps pointing out in which these breakthroughs can’t or shouldn’t exist, they’re obviously not going to exist without you. Because no one else can see it, but you can, you need to pave that path forward and make it possible for others to follow suit. If you’re wrong, you tried, you gave it a great shot. The idea was tested. If you’re right, you’ve changed everything. And that’s worth doing.

If there’s a single take home it’s that. 

The second, I would say, is communication is key. It is inherent people can’t see what you see . But that’s not on them. That’s on you. It is your job to make it [00:15:00] possible for them to see it, so that they can understand, and support it. Communication isn’t something anyone’s naturally born with. Some of us are a little bit better than others, but for the most part, it’s a practiced skill. One that you should practice so you can get better at it.

And the third, (this is going to sound a little bit tongue-in-cheek) you need to understand and get comfortable with a company’s natural arc. I tell this to young entrepreneurs a lot, that this does require checking your ego.

A mentor once told me there are three stages in one’s career. The first stage is when no one believes that what you are proposing is possible. The second stage is when people believe it’s possible, but no one believes that you’re going to be the one to do it. The third stage is when people take for granted the advancement is obvious, and no one remembers you had anything to do with it. [laughs] That’s okay. You need to recognize that’s what success looks like. You shouldn’t do this for your ego but to bring a new discovery to light.

Rich McCormick: That was great advice. Can you provide some insight into the current landscape of innovative therapies and technologies, where do you see the field going over the next five years?

Jonathan Thon: The current landscape of biotech is inextricably tied to markets and financing. What can be sometimes a little bit frustrating for all of us, is to keep ping-ponging between these alternate extremes. On one hand, progress will be limited by a dearth in investments.

That’s particularly felt when that investment is not going into less popular fields, or markets that have fallen out of favor. That’s seasonal. Right? On the other side of it, this over-capitalization of select companies, specific industries, or approaches is also not the answer. It stymies creative innovation, and oppresses competition.

The challenge here is the biotech, and life sciences industries are dependent on financial markets moving on a monthly, daily, hourly pace. Whereas biological innovations to proof of concept, to clinical success, to commercial return on investment, happen on five to ten year timeframes. 

Five to ten years is a long time with significant ups and downs. It requires committed investors, with long time horizons and significant risk tolerances. At the risk of likely misquoting Warren Buffet, [laughs] ” Someone’s sitting in the shade today because someone planted a tree a long time ago.” 

The clinical and commercial successes we’re seeing today in gene therapy are being built on investments that were made more than a decade ago. Every one of those are storied companies with moments they felt they wouldn’t survive or overcome across years, YEARS where industries fell out of favor and have only become popular again because of the staying power of these companies, but then finally hit a practical meaningful milestone, and shifted investor interest back into them.

And so, you ask me where the clinical commercial biotech success over the next Five to ten years will be, it’s to be in these companies that were created over this last decade, likely with a deep emphasis in cell therapy, gene therapy, in cell and gene delivery. 

They will return to favor when the markets stabilize. Those same companies able to last through this more difficult period start hitting on some of their meaningful, clinical and commercial proof of concepts.

Rich McCormick: That’s a great insight. You are rooted in academia, but also a successful business leader. How do you balance the pursuit of scientific knowledge and entrepreneurial success?

Jonathan Thon: There’s a place for both. Neither can exist without the other. A lot of supporting industries in between. I found it easier to teach scientists business, than to teach business people science. One thing I feel can’t be emphasized enough is biotech companies will live and die by their science. 

For biotech companies specifically, I see a tremendous amount of value in having scientists in the CEO and executive suites. What I have taken from my experiences is we need smart, ambitious, young scientists in both academia, industry, and across all of those spaces in between to drive innovation. It is in them that we should be investing. Not the seasoned executives with multiple exits under their belts. Let them be mentors, and have new ideas injecting and driving innovation in their space.

Rich McCormick: Jonathan, it’s been a pleasure meeting with you today. Thank you for being a great guest on First In Human. The team here at Vial, wishes you and your team at STRM.BIO nothing but future success.

Jonathan Thon: I appreciate it. Thank you.

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