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EpiBiome Aims to Harness Genomics to Develop Phage-Based Antimicrobials

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SAN FRANCISCO (GenomeWeb) – After graduating from Illumina's Accelerator program in 2015 and raising $6 million in a Series A financing round last year, EpiBiome is working on harnessing genomic technology to develop phage-based therapies for bacterial infections.

The South San Francisco, California-based firm has 25 full-time employees and has also received $300,000 in funding from the Gates Foundation and US Department of Defense to use genomics to identify bacterial resistance pathways, as well as factors that make bacteria less pathogenic.

EpiBiome CEO Nick Conley said that the firm anticipates having phase I clinical trials for phage-based antibacterials up and running for three different indications by the end of 2019.

The idea of developing phage-based antibacterials is not a new concept, Conley said, but previous approaches to identify effective phages were primarily based on trial and error. Essentially, he said, researchers would culture an infection, test phages one-by-one until they found one that worked, and then deliver it. The problem with that approach is that the mechanism was not understood. In addition, he said, there is tremendous amount of diversity among phages, and bacteria evolve resistance against them.

Research into phage-based antimicrobials fell out of favor after the discovery of penicillin, a broad-based antibacterial, Conley said. Recently though, interest in phages has re-emerged as a potential strategy to fight the increasing problem of drug-resistant infections. Phages may have another benefit too, in that they are specific; they don't wipe out everything in their path, so patients will still have a healthy microbiome intact after treatment.

Advances in sequencing technology have also been helpful for the field. "NGS opens so many doors," Conley said. Sequencing phages and bacteria "enables us to understand what happens to the phage, because it is always subtly changing, and it also lets us understand the mechanisms by which bacteria acquire resistance."

Conley said the EpiBiome team is initially working on three different undisclosed pathogenic bacteria with the goal of developing a cocktail of phages for each one.

EpiBiome uses Illumina sequencing technology as well as other undisclosed genomics and automation technology and performs whole-genome sequencing as well as amplicon sequencing. The firm markets a service called EpiPhany Bacterial Profiling, which is amplicon-based sequencing that includes but goes beyond 16S sequencing to identify? to the species level various bacteria present in a sample, Conley said. That service, while "not the core of the business," generates revenue, Conley said.

EpiBiome also has a number of ongoing academic research collaborations, including a phage genomics collaboration with researchers at Ohio State University and a project to characterize the microbiome of dairy products with a group at the University of California, Davis.

But, its core business is to develop phage-based antibacterials. And one major step in that process is to first sequence the genomes of many different phages and bacteria. The EpiBiome team sequences and de novo assembles many phages that have never been sequenced before, Conley said.

Then those genomes are used to study important traits, like the ability of a phage to penetrate a biofilm, Conley said. In addition, bacterial genomes are sequenced both before and after phage treatment to identify mechanisms that enable a specific phage to kill a bacteria as well as mechanisms that bacteria will develop for resistance.

Sequencing the phages and bacteria and understanding the mechanisms of their interactions will enable the company to apply selective pressure to select for mutants with ideal properties, Conley said.

For instance, the firm received a $100,000 grant from the Bill & Melinda Gates Foundation to develop phages that can harness bacteria's ability to evolve resistance. The idea is that by using sequencing to identify both the resistance mutations and the virulence structures, they can select for phages that target a bacteria's virulence structure. Then, in order for the bacteria to avoid being wiped out by the phage, it will mutate to lose its virulence.

Ultimately, a final phage cocktail will include phages that target the original bacteria as well as phages that anticipate how the bacteria may evolve, preemptively thwarting resistance.

EpiBiome is not the only firm in the phage-based therapy field. San Diego-based AmpliPhi Biosciences already has two phage therapies in phase I clinical trials. The therapies both target Staphylococcus aureus, but one is focused on the treatment of chronic rhinosinusitis and the other is for infectedwounds.

In addition, some researchers are using tools such as CRISPR to engineer phages. Conley said he thinks that engineered phages may have a higher regulatory hurdle to show that they are safe in humans and so plans to stick with his directed evolution approach to developing phage therapies.

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