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FDA Turmoil, Biology Mystery On List Of Hurdles For Microbiome Drugs

Xconomy New York — 

In three years, investment has jumped more than twenty-fold in startups developing medicines that change the interactions between our bodies and the bacteria that colonize it, known collectively as the human microbiome.

But as a panel of industry insiders noted yesterday at the BIO CEO & Investor Conference Monday, the field faces several challenges—including lack of biological insight and, now, worry that the FDA will lack the expertise to evaluate this new and complicated class of treatments.

Despite major questions surrounding the field, investment has picked up steam. As panel moderator Simone Fishburn of BioCentury Innovations noted, in 2013 there were $13 million in investments disclosed in microbiome drug developers. In 2015, there was over $300 million—not including the $121 million Microbiome Initiative launched by the Obama administration that year.

Startups across the U.S. and abroad have formed to focus microbiome research into the development of drugs and diagnostics. Seres Therapeutics (NASDAQ: MCRB) was the first to go public in the U.S.—and the first to suffer a high-profile failure when its lead program, to treat C. difficile infection, unexpectedly failed last summer. Seres and several others such as the French firm Enterome, the South San Francisco, CA-based Second Genome, and Vedanta Biosciences of Cambridge, MA, are all plugging away.

Some companies are using live bacteria as the therapeutic. Seres is taking this approach, as are Evelo Biosciences of Cambridge, and Vedanta.

Others, like Enterome and Second Genome, are developing drugs that modify the way bacteria interact with their host’s gut. The potential applications for such drugs are wide-ranging, from infectious diseases to autoimmune disorders to cancer and more. The gut houses the majority of the body’s immune cells, said Evelo chief scientific officer Mark Bodmer. If we can understand how gut bacteria and such immune cells talk to one another, then tweak that communication, it “opens up this concept of a new modality of therapy,” he says.

Yet as Seres found out last year—its lead drug, SER-109, failed a Phase 2 trial that was meant to prime the medicine for FDA approval—that’s easier said than done. Seres officials last month attributed the failed study to two factors: the company didn’t test a high enough dose of SER-109; and some patients in the study didn’t actually have C. difficile infection. Seres has told the FDA that going back to an older kind of test for infection might solve the misdiagnosis problem.

The panelists yesterday discussed other unknowns that stand in the way of microbiome-based therapeutics.  Pfizer director of R&D technology strategy Nikola Trbovic pointed to “a lot of exciting correlations” between our bacteria and our diseases, but said it’s not clear in most cases if the microbiome is actually causing the diseases. In addition, Trbovic said, the microbiome of each patient can vary, meaning it can be hard to predict whether a therapy will have the same effect on each patient.  Synthetic Biologics CEO Jeffrey Riley agreed: “A bug that may be friendly for me may be a pathogen for [someone else].”

Most big drug makers have shied away from too much microbiome-related commitments. Pfizer is no different. The firm has a research alliance and an investment in Second Genome, which is developing a small molecule drug for inflammatory bowel disease. Otherwise, Pfizer has decided for now to “wait and see and actively watch the live biotherapeutics space” rather than make a big investment, Trbovic said.

It often takes decades for biological discoveries to turn into drug development programs and eventually get to market. Gene therapy and antisense therapeutics are two of many examples.

But panel participants argued that the path forward for microbiome therapeutics would be quicker. Unlike RNA interference—discovered in 1998 and yet to produce a marketed drug—or engineered antibodies, Evelo’s Bodmer said, there isn’t a “technical development component” for these drugs.

Once Evelo, for instance, identifies the organisms it wants to engineer as therapies, it can begin making them for clinical trials without having to solve another technical challenge, like how to deliver them. “We’re not forcing physiology into contortions that it doesn’t expect,” he says.

That’s not to underplay the manufacturing and regulatory challenges for microbiome drug developers that get within striking distance of FDA approval, Bodmer said. For example, the biological activity of a live strain of bacteria can change depending on the conditions under which it’s cultured. That makes the manufacturing process—from identifying the bacterial strain to delivering it to a patient—critical. “That’s going to be the real challenge here,” Bodmer said.

Panelists also expressed concern about the regulatory outlook. Evaluating live bacteria as medicine is uncharted territory for regulators like the FDA and the European Medicines Agency. The panelists wondered if the FDA would be able to hire experts or retain the ones they have in the Trump era. Although reports last week indicated the FDA might get an exception to the federal hiring freeze, it remains to be seen if the already short-staffed agency can not only evaluate new microbiome treatments but also write the rules about how to evaluate them.

“Live biotherapeutics [are] very complicated and I think you probably need some experts in there to help make policy,” said Synthetic Biologics CEO Riley. His company is making “small molecules,” or traditional chemical drugs, hoping to avoid some of that uncertainty.

Check out these stories for more on some of the major players in microbiome drug development.