Empress Therapeutics mines microbial genomes for drugs

The microbes that have evolved alongside humans are a gold mine of genetic information. Some of the bacteria living peacefully in our gut and on our skin have enzymes that help create compounds that act on targets involved in human diseases.

Recently, advances in sequencing technologies have made it easier for scientists to access genetic information about the enzymes that make those compounds. Insights from metagenomics—the study of nucleotide sequences from a specific population, like microbes that dwell in the gut—have already led to new biologic drugs.

Now biotechnology start-up Empress Therapeutics is working to apply a similar process to small molecules. The goal, in short: get chemical insights from the metagenome, then use those to develop small molecules.

“Nature has run the biggest phenotypic screen ever, the biggest clinical trial ever,” cofounder and CEO Jason Park says. “You’ve got all this chemistry inside your body that interacts with every possible disease target.”

Park and Sabrina Yang, another cofounder, who serves as Empress’s chief innovation officer, estimate that there are 10²⁴ potential combinations of compounds from microbial enzymes. Empress uses those enzymes to find such compounds but ultimately makes drug candidates via synthetic processes.

To narrow down the possibilities, Empress compares the metagenomes of microbes from people with a given condition with those from people without it. Its scientists feed those data into a computational platform, which identifies clusters of genes that code for enzymes that produce certain chemicals.

Next, the platform finds genetic associations between those compounds and the condition. Scientists plug the most promising gene clusters into other microbes, like Escherichia coli, to figure out whether the biochemical pathway the genes carry out could form the foundation for new small molecules, similar to the way researchers use recombinant DNA and production cells to generate antibodies. Park describes synthetic biology as a tool to get to the initial compounds.

“That was the fundamental thesis of Empress: Can you tie small molecules back to the genetic code?” says Chief Scientific Officer Murray McKinnon, who joined the start-up in January 2023 after a career in Big Pharma.

Empress is beginning with a focus on autoimmune disorders. The communities of microbes in and on our bodies often produce compounds with drug-like properties that interact with our immune systems, Senior Vice President of Biology Joe Kelleher says. It makes sense, then, to fashion drugs based on those microbes’ mechanisms.

The start-up has identified a number of compounds that interact with the immune system. Park describes one orally bioavailable compound that Empress has discovered that modulates or suppresses inflammatory cytokines. Like all of Empress’s drug candidates, it hasn’t yet been tested in humans, but Park suspects the compound will be able to make its way to multiple types of tissues safely, given that it’s a synthetic version of a chemical naturally found in the body. That safety would present an advantage over classic immunosuppressive medications.

Empress got its start as a project of Flagship Pioneering, the Cambridge, Massachusetts–based venture firm behind Moderna and a slew of other biotech companies. Park, Yang, and a team from Flagship—CEO Noubar Afeyan, Executive Partner John Mendlein, and Managing Partner Doug Cole—began running experiments around 2017 and formed Empress soon after. The start-up formally launched in June 2023 with $50 million from Flagship.

Empress now has more than 500 compounds in freezers at its new headquarters in Watertown, Massachusetts, just outside Boston. Executives estimate that they’ll start testing compounds in human clinical trials around 1 year from now. They’re seeking partnerships with large pharmaceutical companies that may be able to use the molecules for diseases other than autoimmune disorders.

Automation is critical to Empress’s goal of scaling the number of programs in its pipeline. The company hired its first automation engineer this summer “so we can do more with fewer people and more with robots,” as Head of Platform Development Dawn Thompson puts it. Thompson joined last August; since then, every process has scaled fourfold, she says. Kelleher, the biology head, adds that the automation also helps create a smaller library from which his team ultimately screens candidates, cutting down on the amount of work needed to find potential drugs.

“People talk about fishing in a stocked pond. We’re fishing in a stocked pond with dynamite,” Kelleher says.