After more than a decade in a leadership role at 23andMe—a company that endured controversy while making a name for itself in direct-to-consumer genomics—Emily Drabant Conley, PhD, acquired the skills (and thick skin) to become CEO of Federation Bio. Like 23andMe in its early days, FederationBio is in a new and highly competitive space. Specifically, Federation Bio is establishing itself in microbiome therapeutics.

Conley tells GEN that although genomics and microbiomics are distinct disciplines, she sees “a lot of parallels.” One parallel is their potential to fundamentally change drug development. Another parallel is that both fields are acquainted with skepticism.

When Conley joined 23andMe, there was still doubt, she recalls, about the role of genetics in drug development. She adds, however, that when she left the company one year ago, genetics had already become “a cornerstone for target discovery and target validation.” Today, she predicts that a similar trajectory, from discovery to clinical benefit, will be achieved by microbiome therapeutics.

Given the doubts that have surrounded the microbiome field from the beginning, particularly with respect to therapeutic development, many people would hesitate to jump in with both feet. Not Conley. She says that she is used to working in a field characterized by skepticism, disruption, and controversy. In fact, she is not only OK with it. She enjoys it.

Different roads lead to the same cure

A drug developer at heart, Duncan Peyton, CEO of 4D pharma, says that his company’s class of medicines, live biotherapeutics, are still drugs. The beauty of making a drug from bacteria, he explains, is that they have evolved to benefit their hosts. The goal at 4D pharma, he adds, is to find those bacteria that have a beneficial impact on disease pathways.

The approaches that microbiome companies take to build their drugs reflect the diversity of the microbiome itself. Some companies engineer a naturally occurring bacterial strain to express genes of their choice. Others focus on metabolites, casting the bacterial cells aside. Consortia, or groups of bacteria, are the choice of other developers. Federation Bio takes the group approach to the extreme, designing drugs with up to 100 bacteria. By contrast, 4D pharma, a relative veteran in the microbiome space, makes drugs that include only one bacterial strain.

Which approach—one bacterial strain versus a consortium—is more likely to work? Sarkis Mazmanian, PhD, professor and microbiome researcher at the California Institute of Technology, says that the lack of data for either approach, or more broadly, for microbiome-based treatments, makes any evaluation of these competing technologies speculative.

Mouse studies, Mazmanian notes, shed little light on the differences between the two approaches, as most research has been done with single strains, coupled with the inherent limited translatability of mice. Another question that remains unresolved, and is likely context dependent, is whether or not strains need to engraft to provide beneficial effects.

Mazmanian doesn’t see enough distinguishing features, at least for now, to favor one approach over the other.

The more, the merrier

Federation Bio takes a “go big or go home” approach to microbiome drug development by building extraordinarily large and diverse communities of bacteria. Why does Federation Bio plan to pack many bacterial strains into its drugs, while other companies use a small group of bacteria or even just one?

It’s a “philosophical difference,” Conley declares. Bacteria live in a dense ecosystem with other bacteria. Based on that, Federation Bio believes that using bacteria to establish the ecosystem, in addition to the drug of action, will allow the bacteria to durably engraft and perform their functions more efficiently. This, Conley says, would be more challenging with a single strain. In her view, it is possible to find a single, magic strain, but putting such a strain into an imbalanced microbiome—an environment that is in a state of dysbiosis—would be “like putting a fish into a tree and expecting it to thrive.”

Federation Bio’s researcher in lab
Federation Bio’s lead program is focused on secondary hyperoxaluria, a renal condition for which there are no approved therapies. The company’s approach is to deploy directly acting microbes along with diverse commensal bacteria that support stable engraftment. This approach, the company says, could be used to treat metabolic disorders, immune diseases, cancer, and other diseases.

Federation Bio’s lead program is a drug to treat secondary hyperoxaluria, a serious renal disease where patients absorb an excess of dietary oxalate. When filtered into the bloodstream, the oxalate can create recurrent kidney stones, which can lead to chronic kidney disease or end-stage renal disease. A small subset of the bacteria in the drug, FBI-001, degrade oxalate. The majority of bacteria in the drug—Conley estimates around 90%—act as supportive strains that help reduce inflammation and improve tight barrier function to aid the process.

One challenge to Federation Bio’s approach, says Conley, is manufacturing a drug that contains so many bacterial strains—something that has never been done before. Mazmanian agrees that manufacturing and delivering dozens of bacteria is “a very different prospect” from that presented by single-strain approaches.

Another differentiator for Federation Bio is its focus on engraftment. Although some microbiome companies do not place the same importance on long-term colonization of the bacteria, and do not mind asking people to add a daily pill to their regimen, Federation Bio wants to move away from chronic administration. The company favors a single course of treatment with the potential for boosters (in the event of a course of antibiotics, for example). Although the data on long-term engraftment of microbiome drugs is sparse, Conley points to fecal microbial transplantation (FMT) studies that show 60% of bacteria are still present five years after treatment.

Conley sees the focus on engraftment as part of the opportunity to be found in the microbiome. It’s a living organ, she explains—a “self-replicating therapeutic.” Drawing a parallel to gene therapy, Conley says that it is ideal to give people strains of bacteria that will replicate inside their body without further intervention. Conley adds that it is this aspect of microbiome drug development that she finds really exciting—to alter the microbiome in lasting ways that benefit patients over time.

One and done

Peyton had worked together with Alex Stevenson, PhD, CSO of 4D pharma, for years before they started thinking about starting a microbiome company. Before joining 4D pharma, they developed Fintepla, a drug for the treatment of seizures for people who have Dravet syndrome and who are older than two years of age. (Fintepla received FDA approval a year ago and is now sold by Zogenix.)

Fintepla consists of fenfluramine, which is, Peyton remarks, “quite a dirty drug.” Due to deaths associated with its use, it was black labeled and ultimately taken off the market. But Peyton and Stevenson found that in small doses, Fintepla is effective for people with Dravet syndrome. Peyton told GEN that while Fintepla was going through clinical trials, he always had the toxicity of the drug in mind. Because of this, Peyton has always emphasized safety. He says that he’s not worried about the microbiome drugs. He relates that among the 500 patients dosed by 4D pharma, not a single serious adverse event has been observed.

In 2011, a year before the FDA defined a “live biotherapeutic,” Peyton came across the work being done in the microbiome by Imke Mulder, PhD, research director at 4D pharma. At the time, Mulder was working on bacteria to add to animal feed that would interact with the immune system of pigs to make them less prone to diseases of the gut. Upon learning about Mulder’s work, Peyton and Stevenson said, “hold on a second—we think there is a drug in there.”

They started investing in the research, which led to the formation of 4D pharma in 2014. Since then, they have been working on turning bacteria into drugs.

Peyton and Stevenson come from the business side of drug development, having previously run a healthcare investment management company. Peyton says that they had a lot of success (and a lighter workload). But they saw the opportunity that the microbiome held and wanted to build something.

Based in Aberdeen, Scotland, the company is making progress with 1,163 patents, 85 employees, and its own manufacturing facility. The company is currently enrolling and/or dosing patients in trials for cancer, irritable bowel syndrome, and asthma. A Parkinson’s trial will be starting in 2022.

The 4D approach, not surprisingly, is a traditional drug discovery approach with a focus on functionality. The drugs consist of single bacterial strains sourced from the human gut. Unlike other microbiome companies that genetically modify their drugs, 4D pharma “doesn’t mess around with them.” The drug is a single strain of bacteria in a capsule, twice a day. That’s it.

Peyton says that this is what some people are missing about the microbiome. Everyone thinks about it at the species level, he says, when actually “they need to be thinking about the functionality level.” This approach makes sense to Peyton, despite other companies focusing on consortia-based drugs. He asks, “How many drugs do you take that have more than one active ingredient in it?”

Whether they rely on one bacterial strain or assemble many strains, whether they set up long-term engraftment or arrange for daily doses, or whether they treat cancer or Parkinson’s, microbiome companies are busy trying to figure out which keys will open up the next treasure trove of therapeutics.