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Would you be able to walk us through your career path up till now? What were some of the key experiences that led you to co-found Inhibrx?
My background is a little different from some of my peers. Out of school, I started on the executive search-side, and so I worked with a number of biotech, medical device, and life science tool companies. When I was doing that, I put together the senior teams for over 40 companies. That was earlier in my career.
I went from there to the investment side, and, for eight years, I ran a biotech investment fund that was strategically focused, but in public entities, primarily. We initiated that after the dot.com crash, starting in around ’02, or ’03. That experience led me to believe there was a better way to execute drug discovery, drug development, and run a biotech company, because I just didn’t like some of the things I saw.
That’s what led to starting Inhibrx in 2010. I wanted to create an environment where teams would be better incentivized, which would in turn allow them to remain focused and increase efficiency. And that’s been my last 15 years – building Inhibrx.
The field of engineered antibodies is relatively crowded. What do you see as Inhibrx’s approach, and what sets it apart from competitors?
From the very beginning, with my two co-founders on the scientific side, Quin Devereux and Brendan Eckelman, we took an approach where we looked at it from a target biology point-of-view. Our belief was that the best targets are known, but how to drug it properly wasn’t quite so clear.
Building from there determined what platforms and technologies we developed internally. So, we approached the problem differently. There are a lot of companies that engineer antibodies, and due to their core expertise being the engineering of antibodies, they start with that platform, before going from there. We started from the target biology-side and then created the tools that we needed to build for each of those aspects.
One of our initial programs was for alpha-1 antitrypsin deficiency. No one had been able to make recombinant AAT. We were the first to do that. We engineered it to be therapeutically maximized, but that wasn’t overly challenging for our team. The challenges were more on the CMC downstream side. We had to figure out a lot of the downstream, because you had to purify this protein in such a way that it wouldn’t misfold and become inactive. That was a big innovation to figure out! And then, you had to ensure you could scale it, because you had to make a massive quantity of it.
That program was acquired early last year through an acquisition spin-co with Sanofi.
We had a lot of expertise in the DR5 target which led to our oncology portfolio. My co-founder, Quinn, wrote one of the defining papers on that pathway, as a postdoc. He developed the first DR5 antibody to go into the clinic for Novartis. So, that was an area where, up until we read out our successful registration study, about a week and a half ago, there was a 25-year period of multiple programs failing.
Just from understanding that biology, and where the known problems that people had already run into were, it led to the creation of our single-domain antibody platforms. We knew that we needed to precisely define valency. We then used that platform to go after other TNF receptor superfamily members - sitting more in the immuno-oncology space. Based upon that, we had several programs that went into the clinic.
As a company, we just continue to innovate and look at new ways to tackle known targets. Currently, we have unique ideas related to T-cell engagers. We are also developing a highly engineered IL-2. We are always evolving. But what I think’s unique, for us, is that we start from the target biology-side and then build the toolset for the problem that we need to solve.
So, effectively, coming at the problem from the other side, but also working iteratively on top of everything that has come before?
What I’ve seen happen is that, even if you have a unique antibody engineering skill, it always looks like it could be applicable to many things. It really never turns out that way. It’s usually applicable to one thing, and, hopefully, you’re lucky enough to find the thing with which it works.
I think that’s how we look at it. We’ve created unique platforms and tools to help us, but, often, they’re relevant for one thing in particular. Drug discovery is hard - especially in oncology!
What were some of the lessons from the lead INBRX-109 program, and how is that shaping future designs?
Well, I think we took a lot of lessons from everybody else’s failures in DR5, which really helped us. We knew exactly what we needed to overcome. Our research and translation team did a great job with that.
You come away with an appreciation of how hard this is! You really grasp that, when you come into the clinic with a novel target, there’s so much that you don’t know. You have to appreciate everyone who came before you, take those lessons, and apply innovation on top, to try to solve the problems that led to failure. That’s the key lesson learned from DR5.
The other key piece of the puzzle goes back to how we looked at things from the beginning - the best targets are known, but how to drug those targets isn’t. That’s the challenge.
You learn a lot from positives, but maybe even more from negatives. Any failures that really stuck, and how quickly do you know to stop pursuing an idea?
There’s a ton. To get to the four programs we initially put into the clinic, we probably worked through 90 ideas in research, to whittle it down to those four. So, obviously, most things we tried didn’t work.
It really depends. Some things can come together quickly, because, sometimes, you see the issue that needs solving right away, and you can either solve it or you can’t. If you can’t, you just move on. Some things take a few more steps.
Upfront, you need to know the key things that you should be seeing. We also wanted to make sure we didn’t introduce bias, so we ensure we are always working on a number of different ideas at all times. The programs that are overcoming the challenges - those are the ones that get attention and are pushed. Many, though, just die their natural death from not being able to overcome the issues that we were trying to address.
You mentioned your co-founder, Brendan. He’s recently moved on to co-found another company. How has a CSO departing changed your R&D?
I think Brendan was really intrigued by a unique way to develop ADCs, but that was going to take longer. It just made more sense to spin that off and let him go and do that on his own. Part of our team went too. It’s kind of a natural progression.
We still have a really tight team with a lot of tenure that has really advanced over the last 15 years. One of our goals going into this year was to focus everything, in terms of research, on programs that would fly or die as they advanced to the clinic.
My belief is that you’re best when you’re smaller. Keeping smaller, tighter teams is better than getting too big. So, it’s just natural evolution. From the beginning, we wanted Inhibrx to stay smaller. You see this in biotech, pharma and tech - when a company is small and focused, they do amazing things. Then after some success, they grow too large and can’t innovate anymore. So, our focus is to always keep it smaller and focused.
Can you see the technology having potential outside oncology?
Yeah, absolutely. We did a collaboration with a new company called Phylaxis, to create a unique antibody for severe allergy. We were really busy internally, so we created the antibody, and then handed it off to Phylaxis to do the mast cell biology. It went into the clinic last month.
With our T-cell engager platform, the primary focus is solid tumors, but we also have a big effort going into B-cell depletion, which is more immune-inflammatory. The engineered cytokines, like IL-2, are still oncology.
From time to time, we will venture out of oncology when the target biology leads us there, like with the alpha-1 antitrypsin program and the severe allergy program. We will have an immune-inflammatory program heading into the clinic over the next year-and-a-half to two years.
How do you see current market conditions shaping Inhibrx’s runway and outlook?
We’ve always been very careful with dilution. In biotech, that’s one of the biggest problems - you need to keep raising capital. You see companies’ market caps go up dramatically with successes but share prices don’t move a lot.
We’ve always had high internal ownership at Inhibrx, from the very beginning and so we have always been aligned with our shareholders’ best interests. Part of the reason that we executed the Sanofi deal was to take dilution off the company, because the AAT program was great, but wildly expensive. If we had kept it, we would have raised close to half a billion last year, and half a billion this year. It’s wildly expensive to raise capital in biotech where market caps are comparatively a lot lower.
The deal was structured so that, by selling the program to Sanofi and doing the spin-co, Sanofi capitalized the newco with 255 million dollars, which really gave us the runway to execute the INBRX-109 program without raising capital. And now, after the success of that program, you see it reflected in the share price.
Our philosophy is to focus on innovation, clinical translation, doing things efficiently, and then transacting de-risked programs with large drug companies. It’ll be the same with DR5 - we will transact that with a strategic partner in the coming months.
You’re mostly looking to research, de-risk, then sell to larger players, like Sanofi?
Exactly. That’s our focus – complete the innovation and translation internally, de-risk the asset in the clinic, and then move it into the hands of a major drug company that has the proper commercial footprint for the drug. It also works well for shareholders because they realize those monetizations too.
Do you think you’ll get too big, become big pharma, and can’t innovate anymore?
No. That’s why we keep resetting. It’s, in part, why Brendan spun off his group. We’ve really learned that there’s a certain size that’s optimal. We’re on Inhibrx 2.0 now. I think, in the coming months, we will transition to 3.0. That’s the plan.
What’s Inhibrx’s competitive edge now that you're standalone post-Sanofi?
I think our edge is on the research side - being really innovative, solving problems that others haven’t solved and not being scared to go after targets where everybody has failed, because you learn a lot from that. Anytime you start something new, there’s a lot that you don’t know.
It’s also being efficient and making a great return on the capital our investors have put in. It creates nice payouts, internally, too. Marrying that efficiency and problem-solving with clinical translation and de-risking is key.
What core principles would you like to share with the next generation of biotech leaders?
I would say: don’t be scared off by targets with a lot of failure. Capital is expensive and the journey is tough. We’re possibly one of the ten percent of companies that went public, between 2019 and 2021, and have returned capital to investors with a positive return.
You need to be mindful of how you operate - the risks you take; your capital efficiency; having a clear path to de-risking; and being able to monetize effectively. The only way to keep investors in the sector is by producing good returns. You can’t just do cool science. It has to translate into something monetizable, because, as I said, it’s wildly expensive. Investors step up, but they need to see the returns too if we want to see the sector healthy and continuing to bring great innovation.
