First in Human Episode #44 featuring Max Darnell

Max Darnell, Ph.D., CEO and Co-founder of Molecular Therapeutics.

Max Darnell, CEO and co-founder of Modulus Therapeutics, takes us through his thrilling journey from bioengineering and systems biology to launching a biotech startup. Max unveils how his team’s curiosity and motivation, along with their high throughput discovery platform, are revolutionizing cell and cell therapy component designs. Hear how Modulus is making strides in the autoimmune space and harnessing the power of DNA barcoding and sequencing to transform traditional assays into high throughput screens.

Rich McCormick: [00:00:00] Hi. I’m Rich McCormick, Executive Vice President of Clinical Strategy here at Vial. Today, I have the pleasure of welcoming Max Darnell, CEO and Co-founder of Modulus Therapeutics, to our First In Human podcast. Hi, Max. Would you mind telling us a little bit about yourself?

Max Darnell: Sure thing. Thanks for having me, Rich. It’s a pleasure to be here. I’m the CEO and Co-founder of Modulus Therapeutics. My background is in bioengineering and systems biology. I did my PhD at Harvard, working in Dave Mooney’s lab, and came out to the West Coast, to Seattle to do a postdoc at University of Washington in single cell and functional genomics methods development.

Had the chance to join the Allen Institute for Artificial Intelligence in a startup incubator they run there, where I met my co-founder Bryce Daines. That was where we ended up spinning out Modulus from. So, I’m excited to tell you a little bit more about the story today.

Rich McCormick: That’s a great segue. What inspired you and Bryce to start Modulus? And then tell us about the Allen Institute of Artificial Intelligence and how that played a role in your vision.

Max Darnell: With the incubator network, AI2, we had a mandate to broadly explore ideas that were at the intersection of high throughput biology and computation. That incubator provided, an environment to do that exploration and provided a little bit of structure.

Being in Seattle, a cell therapy hotbed, the cell therapy application space was just staring us right in the face. We started to dig into the ways that cell therapies were being conceptualized and designed. We realized we were in a pretty interesting spot in the cell therapy, industry evolution.

At this point, late 2020, we had a handful of CAR T-cell therapies that had been approved in, oncology. and we also had just an ever-growing list of cell engineering tools at our disposal. We realized there was a key gap in information on how to best deploy those tools. Say you have new fancy gene editing. Which genes do you edit? You have new protein engineering methods. What signaling pathways do you need to drive in order to get some increased function out of your therapeutic?

So the founding thesis of the company was if we could build a high throughput discovery system for cell therapies, we would be able to dramatically open the aperture of functionality we could get into these therapeutics moving forward. And, ultimately, hopefully, be able to bring cell therapies forward to the clinic faster as well.

Rich McCormick: Modulus started in 2020. What key milestones or achievements stand out for you over the last three years? What do you envision for future growth?

Max Darnell: I have to start with our team. I’m extremely excited and proud of the team we’ve built. We brought in veterans from the cell therapy industry, as well as, people from, cutting edge molecular biology labs, and computational backgrounds for which this is their first cell therapy foray. Overall, this is a team that is curious, is driven, and is motivated to do things differently. It’s just been a pleasure to work with all these folks, thus far. That’s definitely number one.

On the technical side, in the past two or three years, we’ve definitely been successful in building this high throughput discovery platform. We’ve been able to discover various designs for cells and cell therapy components, which would be very difficult or, if not impossible to discover in other ways. That’s been really satisfying. 

We’re at a pivotal moment in the company’s life cycle right now. We are starting to translate this discovery platform into our own internal therapeutics programs. We’ve recently kicked off our first program in the autoimmune space, hoping to be in the development candidate stage early next year. That, hopefully, is paving the way for us to do a lot more development in the future.

Rich McCormick: It’s great to be able to describe a team as curious, especially in this space. It’s a great characteristic for a team to have. Max, can you explain how your convergent design platform works and how it’s revolutionizing the field of cell therapy?

Max Darnell: Absolutely. When we think about how we want to design therapies, we start with the objective, first. Typically, it’s the question of: what is the function that we want to dial up or dial down to improve the efficacy or safety of one of these cell therapies? The bedrock of that are the functional assays we have at our disposal.

In the cell therapy industry, there are a handful of these gold standard assays folks use to characterize function. This could be how well does your cell therapy kill target cells, or persist in harsh conditions, these sorts of questions. But typically, these assays are run, one or two or several designs at a time.

What we’ve done is we’ve used techniques like DNA barcoding and sequencing to convert those gold standard assays into high throughput screens. Instead of looking at a handful of candidates at once across different wells, [00:05:00] we can look at tens of thousands of candidate cell therapy designs just in a single well, all in parallel, measuring that functional, information. 

A quick example is in T-cell or natural killer cell therapies, exhaustion is one of these key criteria people think about a lot. If you expose your cell to target cells over and over again, your cells become exhausted and can’t kill the target cells after some point.

We had a hypothesis that we could design chimeric antigen receptors, CARs, (the CAR in CAR T) that could increase that time to exhaustion. So we took a gold standard functional assay that measures and characterizes exhaustion, did a high throughput screen of several thousand CAR designs, and were able to identify a handful of CARs that actually doubled the time to exhaustion in these, NK cell therapies is what we were looking at. That’s a more concrete example for you about how the platform works.

Rich McCormick: That’s really interesting. Thanks for elaborating. Would you mind talking through how modular design is utilized to create customized DNA cassettes for immune cells? What are some of the real world applications for this approach?

Max Darnell: “Cassette” is the operative word you said there. We view the cassette as the DNA operating instructions for the cell. Each of these cells that we’re working with in cell therapy have some interesting native functionality that we’re using as the basis for the therapeutic. Then, we’re doing some engineering on top of that to enhance that functionality or redirect it.

The cassette is the set of instructions that’s encoding the secret sauce of how to enhance that baseline function in interesting ways. The way it works is we perform these high throughput discovery experiments, such as the ones I just described. Eventually, the interesting things coming off of the platform get mixed and matched into these sets of components that can all be expressed simultaneously inside your cells.

We leverage that architecture in two different ways. The first is by working with partners to enhance their own cell therapy designs. We have a lot of discovery capabilities. There’s absolutely the potential to work with partners to drive different functions that they might be interested in.

The second is to use these cassettes as the basis for our own internal therapeutics programs. Of course, in a cell therapy, you have the cell manufacturing process, you have your operating instructions for what you want that cell to do beyond baseline. Something we’re excited about is the very modular nature of some of these cell therapies, where we can use a common manufacturing process across programs, a common DNA cassette architecture across programs, and then from program to program, what we’re doing is we’re just swapping out different components.

This is why we think, in the long run, despite the fact that cell therapy, right now, is not the most scalable modality, if designed correctly, cell therapy can actually be very scalable.

Rich McCormick: As you continue to pioneer the field of cell therapy design, what are some of the more promising developments or breakthroughs that you see coming in the near future? What kind of trends are you currently following?

Max Darnell: In the last decade, or so, this CAR T paradigm has dominated the cell therapy space. When you think about CAR T, you think about mounting a dramatic inflammatory response against a large number of cells. You’re targeting cancer. There’s a lot of cells there to kill. You need a large therapeutic response to make a dent.

What we’re starting to see now is through different types of engineering, different cell types that are being the basis for these therapies beyond T-cells, and new indication spaces like autoimmunity, where cell therapies are starting to be at least partially de-risked, I think there’s going to be an opportunity for one or more new paradigms.

 Inside Modulus, we have kicked off a program in the autoimmune space. The situation is very different than in oncology. The patient is already sensitive to inflammation. The number of target cells to kill is significantly less than in the oncology setting.

Perhaps you want a cell therapy that acts a little bit more like a traditional drug, where you can administer it, it has very controlled kinetics, it goes in, does its thing, and a week later, it’s completely gone. The Clinician is very in control of that process. That would be a really interesting paradigm that would open up new application spaces and we think one that could also broaden the accessibility of cell therapy. That’s one of the things I’m looking out for. 

Rich McCormick: Success can be defined in a lot of ways. What’s your personal definition of success as a leader at a biotech company? What advice would you have for aspiring entrepreneurs [00:10:00] and scientists looking to make an impact in this space?

Max Darnell: Everyone in the industry is motivated by patient impact. Whether you are doing late stage clinical trials or early stage discovery, that’s the north star for everybody. And, we are very much included in that.

Something else that motivates our team, beyond any deal we might sign, or any particular therapeutic program we might try to advance, is just the notion that this is an interesting, exciting space, but there are paradigms that need reinvention and evolution. The fact we’re contributing to that and doing something new is something that very much motivates the team on a day-to-day basis.

Even if we never get a drug into the clinic. The fact that we have injected new thinking, and hopefully fresh, energy into the system is something that gets our team out of bed every morning.

 In terms of advice, I would say, not only peg yourself to that north star of patient impact, but figure out how you can motivate yourself via the process as well. Enjoy the process and get motivated by those little things you’re doing every day to march towards that north star.

Rich McCormick: I’m sure you’ve put in countless hours since starting Modulus. How do you maintain a balance between professional commitments and your personal wellbeing when it comes to managing the pressure that comes along with being a CEO of a biotech company?

Max Darnell: Well, you unfortunately can’t have it all [laughs]. There’s a saying, “You can only do two or three things at any time in your life well.” that has definitely held true for me [laughs]. I’ve learned, though, there are definitely enough hours in the day if you are just honest with yourself about what those priorities are and you cut out a lot of the rest.

For me, obviously with Modulus, that is super important. I also have a family, two young girls, and I prioritize physical fitness, because that allows you to do the rest. Unless other activities are aligning with any of those three, they tend to be pretty low priority. But, you can make it all work. 

Rich McCormick: Max, it’s been a pleasure meeting with you today. Thank you for being a guest on the First In Human podcast. The team here at Vial wishes you and the team at Modulus Therapeutics nothing but future success.

Max Darnell: Thanks a bunch, Rich. Great questions. Really enjoyed it. Good luck to you guys, as well.

Rich McCormick: Thank you.

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