First in Human Episode #28 featuring Trevor Martin

For episode 28 we connect with Trevor Martin, Co-Founder & CEO of Mammoth Bioscience.  Learn how Mammoth is utilizing CRISPR technology to develop innovative genetic treatments, and what challenges a platform biotech company like themselves faces as they grow and work towards their goals. First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder & guest host Co-Founder, Andrew Brackin. Episodes launch weekly on Tuesdays. 

Simon Burns: [00:00:00] Trevor, thanks for joining us on First In human. 

Trevor Martin: Thanks for having me. 

Simon Burns: Tell us about Mammoth. We’d love to hear the backstory. 

Trevor Martin: Mammoth was founded five years ago by myself and the inventors of the CRISPR Technologies we work with, Jennifer Doudna, Janice Chen and Lucas Harrington, from Berkeley. The genesis of the company was really this idea that there’s this whole universe of CRISPR technologies that go beyond the ones that people are most familiar with, which are things like Cas9. For those that aren’t familiar with CRISPR, these are technologies that allow you to actually engineer genomes.

I think of them as these search engines for biology, where you can actually program these CRISPR technologies, tell it to go somewhere in the genome, and then you can leverage that to do a wide variety of things. You can edit genes in different ways by either knocking them out, inserting a sequence, maybe even changing a single base pair.

At Mammoth, we’ve also pioneered this technique of even using them to send out a signal flare to say that they successfully found the sequence of interest. The legacy technologies like Cas9 have now seen really immense progress over this time period. There are actually patients walking around today who have been dosed with these legacy technologies.

When Mammoth was founded, we really saw that there remained these grand challenges in CRISPR. Things like, how do you actually deliver the CRISPR technology into the body, especially beyond the liver? How do you do the right type of edit once you’re there? One of the big things that we’ve pioneered at Mammoth, starting even not just five years ago, but many years ago through my co-founder’s work at Berkeley, is this area of what we call ultra compact systems.

These are systems that are really small physically relative to the legacy systems like Cas9. That can be very important for effectively delivering, whether that’s viral or non-viral. That allows us at Mammoth uniquely to go beyond the liver, to go extra hepatic and to actually tackle these other tissues that using legacy technologies can be very difficult to tackle.

All for this overarching goal of creating potentially curative therapies for genetic disease. The genesis of Mammoth is this recognition of the importance of innovation to solve these grand challenges of CRISPR. Now, the evolution of the company has been continuing to deliver on that innovation while getting closer to the clinic.

Simon Burns: One of the challenges a lot of platform biotech companies face is when to partner, how to partner, earlier or later. What have you seen or lessons learned from your perspective on what advice do you have for other biotech companies building platform companies? 

Trevor Martin: In general, it’s the classic problem of a platform is that you can do anything, but, you can do anything, right? There’s different answers at each stage of the journey. Overall though, one of the most important things for the platform is to understand what the differentiation is and what the use case is, and how is it actually going to matter for patients at the end of the day.

Even at the very beginning, you can start to think about that. Maybe you don’t have all the proof points of knowing okay, I go this way or that way. But, you can have a hypothesis about what is going to actually be different for patients. Especially in a different macro environment where people are maybe less risk on and more risk off.

It becomes all the more important to be able to really articulate. Let’s assume everything works wherever you are in that platform journey. What is the product hypothesis you have? What are you going to do in the clinic that is going to be differentiated from other platforms from people already in the space from other modalities or techniques?

That’s a really important question to answer. Platforms are awesome, but at the end of the day, you need to have a very compelling narrative bit for yourself and of course for investors around. Because this platform exists, what’s going to be possible clinically that wouldn’t be possible otherwise? And, really zone in on that. 

Maybe the top application of that isn’t what you do first. Maybe there’s technical reasons why you wanna tackle something else first. But, there should be a clear narrative around how that’s helping you build to that differentiation. You can’t have just technology for technology’s sake, obviously. Innovation can be super cool and exciting. That’s all correct.

But you need to combine that with an understanding of given that this innovation succeeds and we drive things forward, let’s say like ultra compact systems, what’s going to change in the world because of that, that’s really important for patients and ultimately, for creating new drugs for them. We’ll be able to go extra hepatic, go to tissues beyond the liver, and actually have potentially curative therapies, there. 

Simon Burns: Picking your right pharma partner is also a key challenge. It takes months or quarters just to get things started in often cases. Have you thought about finding the right partner to build the technology with? 

Trevor Martin: That’s a really important question, as well. At Mammoth, we have two great foundational partnerships with Bayer and Vertex. Those are exciting for a couple reasons. The first one is there’s complementary expertise that’s being brought in. That’s a really important part that, sometimes, from the outside people don’t think about. 

Are they bringing disease expertise, delivery capabilities? What are things that would be very difficult? Or, it’s not your area of expertise to build the technology where you can more likely have a successful drug go to a patient at the end of the day, than if you weren’t working together.

That is how your incentives align. A partnership’s awesome, but at the end of the day, the way the partnership succeeds is by having a successful technology that’s helping a patient. You really have to think about at the very beginning.

It’s going to be a long journey to get there. That leads into the second part, which is the cultural fit. This is a long journey. Things will go well, things will go not as well [laughs]. Do you think you have a robust relationship that can be built so that you can double down and celebrate the [00:05:00] wins and then make sure that you’re working together to mitigate any challenges? 

There’s the alignment around what the patient impact can be and what are you both bringing to the collaboration that can help you get there. The cultural aspect of this is a long journey .Do you want to work together? Do you think it’ll be exciting and uplifting for everyone?

The final component of course is the economics. There are many different ways you can structure these around co-development, co commercialization, or a more standard royalty-based pricing. That starts to get more into the details of what stage the company is at. What is your expertise? What are you willing to spend at this stage and sign-up for? That can change over time. But, I think the first two are always true. You need to be aligned in terms of what the patient impact can be. And, also in terms of the cultural mesh of the teams.

Simon Burns: You are, in many ways, a poster child of the founder led bio movement. Many people think it’s having a moment where we’re now transitioning from the more traditional studio model to the founder-led model. Do you think that’s happening? What do you think is going to keep the trend going or reverse it? 

Trevor Martin: I think always examples of success. “Success” here being measured as getting patients the treatments and diagnostics and beyond that they need. That’s going to be the ultimate arbiter. Are you able to create, especially, differentiated products and therapies and, bringing these technologies to places that, maybe, are even more challenging or riskier than going down a traditional path. 

The other part to it that’s exciting to me (other two parts) is, going back to your question about platforms, building a long-term company is something that is a little bit more rare in biotech. There’s this intersection, right now, of founder-led biotech and technological innovation where you do have these platforms that can have multiple products and maybe even get better at building each one as you see success along the way, which is a really important component of it being a true platform.

I think that’s really exciting. At Mammoth, we have this ambition to build a long-term company. To build the next, Regeneron or the next Vertex. That has to be backed up with the right technology platform, the right team, and the ambition. Obviously, the investors and many other things.

In some ways that can be a more risky path, as well, than just going down a more traditional flip and maybe even preclinical and just take stuff away and let the big companies handle it from there. It creates a rare opportunity to A: have a bigger impact and actually see the technology reach its full potential. And B: to build a lasting company on the back of that in ways that haven’t occurred as much in the past for whatever reason. That is a really exciting element to it. Can we build lasting biotech companies with this new model where the founders are helping lead the company in addition to really experienced executives who know what they’re talking about, and have done it before.

That’s the unique combination that we’ve tried to build at Mammoth. Having the founder-led ethos combined with really deep experience and knowing these are the things you should look around the corner for. That’s a very powerful combination. It not just being necessarily even one or the other. 

More generally, one good thing for the ecosystem is that there is a lot of innovation going on in biotech, right now. The more backgrounds and walks of life can be involved in biotech entrepreneurship, is an immense benefit to patients at the end of the day. Because, regardless of the macro conditions in previous times, maybe in the early two thousands, the macro conditions were bad and also, oops, we sequenced the human genome and we don’t necessarily know what to do with it. 

So you have this double whammy here. Whatever macro conditions are bad, good, sideways. There’s never been a more exciting time for looking at what’s happening in biotech and, actual platforms that can help patients. The more opportunities we have to actually bring those forward, and I think founder-led is an important part of that, the better benefit for society.

Simon Burns: Let’s talk about macro. XBI hit a bear market before the rest of the market. It’s been a long time that we’ve been in the bear market. How are you advising people to manage it? When do you think this is going to shift? Do you have a sense? 

Trevor Martin: I’m an eternal optimist. I’m always thinking it can shift. In terms of planning and driving things forward, you have to assume it’ll stay the same or get worse. What’s the phrase? It’s always darkest before pitch black. You have to have that combination, in my opinion, of relentless ruthless optimism and planning, and just assuming good technologies and the best teams will get through whatever macro environment.

At the same time, making sure that you’re planning and not assuming that there’s going to be a magical change in macro conditions and that’s what’s going to unlock something. I think that’s a very dangerous thing to think.

Simon Burns: And lastly, maybe, as an internal optimist, you can give us what you’re most excited about in 2023, both for Mammoth and also for all things biotech?

Trevor Martin: For Mammoth, continuing to move closer to patients. At the JP Morgan conference, where we gave a talk this year, we talked a little bit about some of the items, things like, NHP studies. Especially, driving forward things we call CRISPR plus modalities.

These are non-double strand break methods, like base editing, gene writing, and epigenetic editing. Combining that with our ultra-compact systems so you can actually do, all in one delivery, even extra hepatically. Those are some of the things that we’re excited about, coming up. 

More generally in the biotech industry, it’s just the immense amount of innovation coming out of all sorts of areas, especially academia, and the impact that can have for patients. There’s a bunch of different trends in synthetic biology, including what we work on at Mammoth, like CRISPR, continues to advance.

Now, we’re seeing better predictive methods on the statistical side for understanding the basis of disease. We’re getting ever bigger sequencing data sets that we can feed into that.[00:10:00] There are all these different trends that will come together in very interesting ways as we become better at both engineering, understanding, and creating the building blocks of life. 

It’s hard to predict even what necessarily comes out of that. But, the one thing you can predict, is that if we play our cards right and we do have diverse backgrounds, many people that are interested in leveraging these technologies beyond the lab and bringing them to patients, it’ll be a much better world we live in 10 years from now than today. 

Simon Burns: I love to hear the internal optimism and excited to see what the progress in ’23 holds for you guys. Thanks for joining us on the podcast. 

Trevor Martin: Thanks for having me.

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