Just like Goldilocks in the fairy tale of the Three Bears prefers her porridge, our cells need the timing and amount of gene expression to be “just right.” If the output of a gene is too hot (upregulated) or too cold (downregulated), the very real story of disease begins to unravel.
So far, much of the genetic disease landscape has been approached with therapeutics that inhibit or erase the activity of a specific gene or protein. Yet, there has been little, if any, progress in the ascent of medicines that can restore lost gene expression.
Named after the final basecamp on the way up Mount Everest, CAMP4 Therapeutics is pioneering a novel gene expression upregulation technology to treating hundreds of diseases affecting millions of patients, such as haploinsufficiencies and recessive or loss-of-function diseases. The company was co-founded by two prominent Boston-area academics, Rick Young, PhD (Whitehead Institute/MIT) and Leonard Zon, MD (Boston Children’s Hospital/Harvard Medical School).
Josh Mandel-Brehm is President and CEO of CAMP4 and holds a dual appointment as an entrepreneur partner with Polaris Partners. He spent eight years in business development roles at Sanofi-Genzyme and Biogen before taking the reins at CAMP4 in May 2017. GEN Edge spoke with Mandel-Brehm about how CAMP4 has climbed through several different stages and iterations to land on the path of how it intends to scale the hard-to-reach peaks of genetic medicine.
GEN Edge: What’s the origin story for CAMP4?
Mandel-Brehm: The company was founded around 2016 by Rick Young and Leonard Zon. Rick and Len are longtime collaborators; they each have their own companies, but this is the first one they’ve done together.
Polaris has this neat meeting down in Florida they’ve been doing for almost two decades, hosting a mix of great entrepreneurs, scientists, and business people. There’s always a few interesting ideas that come out of those meetings that turn into companies, and this was one of them. Like many other companies that Polaris invests in, it’s okay that it didn’t necessarily have a complete business plan. What was important was that it had great science and a point of view on the uniqueness of how to use that science.
Rick Young is the guru of transcription and finds everything that happens in the nucleus interesting. Leonard Zon is a cell therapy and cell signaling guy, and to study that, you also need to understand what’s happening in the nucleus. What they were interested in is that technology had gotten to the point where you could use different next-generation sequencing technologies on human cells to create maps of how cells are making decisions, meaning you could show the architecture of the DNA in the nucleus: the loops of DNA, which are control centers, which enhancers go to which genes, and which transcription factors are involved in transcription. Then you could use those nodes and connect them to cell signaling pathways to create maps.
This had a considerable lab component, meaning you had to learn how to do this at scale and in human cells. The other piece was you generate the data, computationally fill in the blanks, and make predictions quickly about which target we want to go after to move a gene or a strategy. So, the basis of the company was creating this platform that allowed you to make these cells. It was a hybrid of good old-fashioned, sophisticated biology meets computation, and that they were successful in bringing you together. From a business model, it’s like any other exciting area of science. You can kind of point it in a lot of different directions.
GEN Edge: What directions did CAMP4 consider?
Mandel-Brehm: When I joined, they were interested in making a business model out of selling this information to big pharma and small companies in their area of interest. At the same time, we were selling these maps, the idea was you get revenue, and you build a bigger and more extensive database. We learned along the way that although the maps are interesting and valuable, the business model is tricky to get off the ground, and it didn’t feel like the best use of the technology.
For the next generation, we learned we needed to activate the maps. We need to add small molecules, which we call “perturbagens”—things that shut off or antagonize different signaling pathways to see what the maps would do. We started learning how to activate the maps and test them in different ways and ask additional questions.
We tried to pick [molecules] that were either on the market or in development because we wanted it to have practical implications. Many were cancer drugs, and what we found, which is not very earthshattering, is that if you use those drugs at lesser concentrations, they’re still quite efficacious, and you can start to tease out the pathways that are working. We began to explore repositioning around this, but it’s challenging to get a big company to out-license their programs based on just preclinical data.
Behind the scenes, Rick Young started working on a very new, interesting area of biology called condensate biology with Phil Sharp and Tony Hyman. This caused Rick to rethink his understanding of transcription. It wasn’t just a biochemical problem anymore—now, it involves physics and biology. One interesting thing that Rick came to appreciate was that there is a class of RNAs that participate in this condensate biology that seemed to act very specifically on nearby genes. They’re like the gas and the brakes at the same time. They’re not like the classic non-coding RNAs or miRNAs that act pleiotropically—they’re shorter and don’t last very long. They operate in these little control centers. If you wanted to identify them and characterize them, our maps are perfect for them.
It became apparent to us to use oligos to drug these RNAs for genes of interest to see what would happen. It worked like a rheostat, and for every gene we tried this on, we could get it to move in both directions at different degrees. We found ourselves wondering, why would you want to down-regulate because there are good technologies that down-regulate the RNAs. However, there’s no upregulation company, and, importantly, if you upregulate too much, you could lead to toxicity in many cases, so you need a narrow range. Our rheostats are perfect for that.
In many cases, especially haploinsufficiencies, small changes have a huge impact. There are about 650 haploinsufficiencies, meaning there’s a very clear understanding of the gene and the disease, but less than 5% have therapies. We looked at that and thought this is precisely where we should use the maps coupled with our expertise in oligos coupled with a major unmet need.
We immediately got to work over a year ago. We built the IP, and when we got convinced that this was going to work, we went out and said, instead of doing a big crossover, it’d be crucial to take the long-term view, to build this big, and make sure it wasn’t just a single asset play. That was the coming together at this recent $45 million round, which is a prelude to the bigger crossover that we intend to get to by the end of this year.
GEN Edge: How is CAMP4 structured to facilitate this venture?
Mandel-Brehm: To be the upregulation company, there are specific functional capabilities that we need to have: to make these maps biologically and computationally, how to develop oligos to get them into the clinic, and how to manufacture oligos. We have the capabilities in-house to do that now. But we are not at the point where we are innovating on the chemistry and making generation 2.0.
We’re standing on the shoulders of giants—Alnylam and Ionis. We’re taking advantage of that for the first generation here, knowing that the biology is going to lead us into ways to think about novel discoveries for chemistry and better versions of regulating genes. That chapter will come for this company, but we want to get some wins on the scoreboard, both pre-clinically and clinically.
GEN Edge: What are CAMP4’s approaches to fundraising, partnerships, and going public?
Mandel-Brehm: Two things need to happen before we go public: (1) a cross-over round and (2) the resources and ability to deliver these oligos. We’re not thinking about lots of little deals. We’re thinking about one massive deal with the right partner that’s very committed to building something in a particular set of diseases or tissue. We’ll probably be ready to do that later this year or early next.
We’re still in the mode of where we have so many programs going and doing different things that we want to have a better feel for where it’s working and what we want to own versus where we’re willing to share right now. We’re being selfish, but the right partnership will accelerate what we’re trying to do.
GEN Edge: What are the major challenges to your development plans?
Mandel-Brehm: For any Series A company to get to the crossover or the next round, [the challenge] is getting in vivo results, showing it’s reproducible, and doing it across the different species or programs. That’s exactly where we are right now. We already have some pretty compelling results, so we’re feeling good. We want to take our time and advance programs both in mice and in primates.
We’re close to the point where we could with a straight face have conversations with people, but we can also afford to be patient with the investors we have. At the end of the day, animal models are a surrogate to where you’ve gotten with the technology. But have you gotten to the point where people are convinced that it’s time to put this in humans? The nice thing is, unlike small molecules where you have a molecule and then you do a lot of Structure-Activity Relationship (SAR), the product is the oligo. We know exactly what to do once we have something that smells like a lead.
We’re a discovery-stage company, but what we don’t have right now is a contract manufacturing organization, for example. We’re ready to build out the clinical function. People make assets; valuable assets don’t make people valuable. Just as important as getting into the clinic and raising capital is to maintain a culture and bring people together. That’s how you make a durable great company because most assuredly, we’re going to bump into problems, and you need people to solve those problems. An essential part of the journey is how you scale, making culture and bringing in great people.
GEN Edge: How does the company balance R&D with getting a product to market?
Mandel-Brehm: When I first got going in this job, and I was a first-time CEO, I thought the idea is to be hugely aspirational—where we’re going to be in 100 years, 20 years, and 10 years. The issue with that is when you’re just at discovery company, you’re trying to figure out what works, and it’s too aspirational. It’s so intangible that it’s almost made up, and you can’t execute it. It’s appropriate for companies to do that when they’re in the clinic and they have more substance, where they have a higher probability of things being successful. That was a lesson learned for me.
Three years is the right amount of time to make a grand statement that we all agree. We want to build a company for the ages. What do we need to do in the next three years to be known as the up-regulation company and to be successful?
From a research perspective, three things are important. One, we want to continue to make these maps that fueled the discovery programs. Two, we want to continue to delve deeper into understanding the mechanism of action and learning more about how this biology is working because we believe that will lead to innovation. Three, we want to set a high bar for innovation, and within three years, we want to publish something that’s never been invented before.
From a pipeline perspective, we’ve looked out to 2024 and worked backward. We want two programs with read-outs, two programs nearing clinical proof of concept, and two IND-enabling programs.
As you transition to a clinical company, it goes anywhere from clinical to regulatory to Chemistry, Manufacturing and Controls (CMC) to more sophisticated and mature financial controls. We’re 45 people today; we’ll be closer to 60 towards the end of the year, 90 next year, and eventually anywhere from 100–150 people. We’re trying to create a place that people are so wildly excited about that they couldn’t imagine working somewhere else.
There is a whole field of disease that we’ve never really been able to think about without upregulation. This is the beginning of an entire revolution to do that. We’re ready to get going there and build this thing out.