Long before today’s aerospace engineers fashioned rockets and space telescope mirrors, bees were using the hexagonal honeycomb structure to achieve the optimum material economy—the highest surface-to-perimeter ratio of any polygon that can be used for tiling the plane. This geometry has fascinated humans for thousands of years, from natural philosophers like the Roman polymath Marcus Terentius Varro reporting on honeybee hives to Galileo’s investigation of how bird bone structure is resistant to bending and breaking.
In a similar fashion to how bees’ instincts to build perfect honeycombs have been incorporated by engineers into the protective carbon fiber panels of aircraft like Boeing 747s, and cars like BMWs, scientists have scoured fungi for the production of therapeutically relevant natural products: the first widely used antibiotic (penicillin), the immunosuppressant that enabled widespread organ transplantation (cyclosporin), and the progenitor of the statin class of cholesterol-lowering drugs (lovastatin). Among FDA-approved drugs, 49% of all small molecule cancer drugs and 73% of all antibiotics originated from secondary metabolites—small molecules produced by bacteria, fungi, and plants (also known as natural products).
Recent advances in genome sequencing imply that there are millions of fungal species on the planet, each with its own genome encoding pathways capable of producing hundreds of natural chemicals. While nature’s molecules have shown to be a rich source of effective medications, translating them has proven difficult due to a lack of mechanistic knowledge of the desired target.
That’s the entry point for Hexagon Bio, a biopharmaceutical company based in Menlo Park, CA, which is pioneering the discovery of medicines encoded in the global metagenome.
Named for the transversely isotropic shape’s natural design and engineering properties, Hexagon Bio’s proprietary discovery platform enables drug development against novel targets, even targets previously considered undruggable. Hexagon’s proprietary algorithms can identify human targets of cryptic natural products, prioritizing among thousands of candidates, and create new chemical entities based on novel chemical scaffolds.
This method of identifying novel secondary metabolites and their cognate proteins (therapeutic targets) from genomic data allows Hexagon to bypass traditional screening methods. While the company’s focus is on oncology and anti-infective medicines, the platform is extensible to immunology, cardiovascular, neurological, and metabolic disorders.
Hexagon was co-founded by CEO Maureen Hillenmeyer, PhD, and Brian Naughton, PhD, the company’s Head of Data. Hillenmeyer previously was director of the Genomes to Natural Products program and group leader at the Stanford Technology Genome Center, and Naughton was founding scientist and vice president at 23andMe, where he helped create the world’s first Personal Genome Service.
GEN originally profiled Hexagon in 2017 after its launch. Recently, GEN Edge met with Hillenmeyer to catch up and discuss Hexagon’s journey into the untapped world of fungal genomes and Hexagon’s vision to lead the next generation of drug discovery companies.
GEN Edge: What are Hexagon’s mission and vision?
Hillenmeyer: Our mission is to discover novel medicines from the global metagenome for patients. That reflects two pieces: first, discovering all the valuable metabolites that nature has encoded and eventually engineering that as well. Second, actually taking them to patients. We’re not just a platform, throwing molecules over the fence to others. We are building drug discovery internally at Hexagon.
Our vision is a world that is better at figuring out targets that need to be drugged for different diseases. Still, as some of them are difficult or undruggable by traditional chemical means, Hexagon brings new chemical matters, especially for those difficult targets. A large part of the vision is letting the world at large figure out targets, and we’re bringing new chemical matter for those targets.
There are an estimated five million species of fungi on the planet, but only 5,000 have had their genome sequenced! That is just a small sliver where all of the big blockbusters in the past of natural products have been found, like penicillin, statins, cyclosporin, and rapamycin. It used to be very laborious to get those genomes, but it has become very easy with advancements in genome sequencing, and the costs are coming down rapidly.
At Hexagon, just over the last six months, we’ve sequenced 25,000 novel genomes, which we’re very excited about. Initially, we were just working with public data and waiting for the public efforts to speed up. Now, we’ve built our own rapidly growing proprietary genomic database. As we sequence the rest, this will unlock all kinds of metabolites and engineering possibilities—and who knows what else! Who would’ve thought of CRISPR? There may be things we haven’t even dreamed up yet that will come out of these sequencing efforts.
Within that, we prioritize based on molecules that computationally are predicted to target human disease proteins. Sometimes we can tell the target of the small molecules. Statins, for example, evolved to target cholesterol. We can see that in the genome sequence that came out. So, if statins hadn’t already been discovered, we would’ve been working on them in the lab because this combination of genomics plus computational biology makes it very obvious that there was something out there that evolved to inhibit cholesterol.
We are very interested in oncology and infectious disease. We’re going through the data looking for others that have evolved to inhibit a particular cancer gene or a fungal-specific protein. Perhaps it’ll become a blockbuster drug.
GEN Edge: What are the nuts and bolts of Hexagon’s pipeline?
Hillenmeyer: We are a mix of genomic and computational biologists building out drug discovery as well as biologists and medicinal chemists taking the early metabolites that we discover and developing them further through testing. The first part of the pipeline workflow is what we call “sequencing the earth.” That’s a small sliver still of the earth, but we’re getting there.
The next step is to identify genes we believe encode valuable metabolites that will become medicines, which computational biologists do. Then, we express those metabolites in the lab. We published some of this when my co-founders and I were at Stanford before launching the company. We transplant these genes from these wild species into baker’s yeast and force it to produce the molecules in the lab. Then we purify those molecules, test them, and then undertake synthesis and medicinal chemistry after that for hits and leads.
We’re still early stage, but we will eventually take these into the clinic. We have oncology and antifungal programs going forward towards the clinic. The next steps for us are to continue to push these two programs towards the clinic while also building out the platform and the database to expand beyond oncology and infectious disease. Long term, we aim to be an even broader company than just oncology and infectious disease. The 10-year plan is to build a next-generation drug company, with this broad platform akin to Moderna, and tackle many different disease areas. This platform is novel, so we’re focused on building out the platform and database to expand beyond those two areas into other disease areas.
We’re going to focus on building our internal pipeline and prosecuting it clinically ourselves internally, eventually building out the team that can do that. But because the platform is so broad, we may also partner. If so, we would have an internal clinical program and possibly have partnered assets at some point. We have amazing investors who understand the opportunity of the platform and its long-term potential. We are all very excited and motivated to build it out and build out our internal pipeline.
Also, our software is awesome! As far as I can tell, it’s unique in the world for capturing all these diverse types of data and surfacing it in a very transparent way where everyone at the company can interact with everyone else, see the data that’s being generated, have important scientific conversations across disciplines because of this software that just makes it all very transparent. For now, the platform, software, and data are proprietary.
Those are some of our competitive advantages. We may go in the direction of licensing or making pieces open source as the whole industry gets a little more rigorous about computation. We’re focused on the molecules. But there are pieces of IP that we developed at Stanford and licensed to Hexagon around the platform.
GEN Edge: How did Hexagon use the $61 million in financing raised in September 2021?
Hillenmeyer: Those funds were to build out the platform and database for discovery, push leads forward, and build out the team. The 25,000 genomes that we just sequenced over the last six months were a big piece of it. Then we’re focusing on a much smaller number of compounds at later stages. We’re still at a very early stage, but we have compounds showing bioactivity in oncology and antifungal assays and pushing them forward.
In addition to that, we’re building out the team. We hired Tara Arvedson, [PhD,] who was previously the Executive Director of Oncology Research at Amgen, as SVP of research, to build out our drug discovery. She has a lot of experience in taking molecules through preclinical development. And we’re continuing to hire outstanding people on both the platform and the drug discovery sides.
We are starting to build out an amazing team in all of those areas—rockstar people with experience in genomics, computational biology, and drug discovery. We’re hiring the next generation of biologists that knows how to code, think about genomics and bioinformatic data, and speak multiple scientific languages. Some of this comes from my background in bioinformatics; I’m pretty deep both in biology and computer science. We’ve been able to hire the next-generation scientist—the biologist who can talk genomics and write code— and, vice versa, the genomics or data scientist who can work closely with biologists and chemists to form an interdisciplinary team.
GEN Edge: What is Hexagon’s charted trajectory?
Hillenmeyer: In 10 years, we want to have built a world-leading drug discovery company. Ten years is not that long, but some companies do it. If we can build up a large enough engine and a bolus of compounds, that’s where we need to be in 10 years to be a world-leading drug discovery company with multiple clinical programs in various disease areas, even beyond oncology and infectious disease.
In five years, we should be in the clinic with multiple oncology and infectious disease programs. At that point, I hope we’re the world-leading company and drug discovery from microbes. Maybe not a giant company yet but established as being the best at making these discoveries that naturally evolved and getting them into the clinic. In one year, we aim to continue this hockey stick trajectory we’re on with the platform and database in terms of the number of genomes that we’ve sequenced to enhance the pool for identifying compounds. It’s a race to these data sets first.
