In other words, the pill didn’t work. Seres stock plummeted by more than 69 percent.
“The results were surprising, especially since the 1b data was eye-popping,” says Roger Pomerantz, the company’s CEO and president, and an infectious disease doctor who has treated many C-diff patients. “We’re now trying to dissect why there was a difference in the two trials.” They’re looking at whether the patient pools differed: Those from the first trial were based on four prominent academic centers, while those from the second came from 37 different sites around the country, including private practices and regional hospitals. They’re also checking if the microbes in the pills actually established themselves in the recipients’ guts.
This failure doesn’t refute the value of fecal transplants, which have already proven their worth in treating C-diff infections. It does, however, show how hard it will be to distill the technique into a more palatable and marketable form. “Obviously there’s something very effective that people are getting when they take the whole stool,” says Diane Hoffmann from the University of Maryland, who is leading a working group that will advise the FDA on regulating microbiome transplants. “Something in there is working. We just don’t know what it is, and it might be hard to deconstruct.”
Or, as genomicist Nathan Pearson neatly put it, “There’s no silver bullshit.”
It’s not even clear if making drugs from stool is the right move. Elaine Petrof from Queen’s University thinks it is. When I was researching my book, she told me that “stool is a stopgap,” and will inevitably be replaced by precise mixtures of well-defined microbes, which can be cooked up again and again to the same recipes. That would be easier to regulate and to check for safety. She and her colleagues are working on one such formulation, which they call RePOOPulate.
But Alexander Khoruts, from the University of Minnesota, felt differently. “The full spectrum of microbes harvested from donors has been designed by nature, and has a proven safety track record in the original host,” he told me. “That’s a very hard benchmark to improve upon with any kind of synthetic.”
The SER-109 story supports his view. It may be that the drug failed because there’s something about the full community of microbes in a donor stool that’s irreducibly beneficial. Pull out one or two beneficial species, and you lose the power of the whole. Perhaps it’s ten species that matter. Or hundreds. Or the chemical milieu of the poop itself.
As Noah Fierer, a microbiome scientist at the University of Colorado, Boulder, noted on Twitter, “Ecology matters.” The human microbiome is not a simple thing that we can tweak by just adding this microbe or removing that one. It’s a vast ecosystem, akin to a rainforest or a grassland. To control it with any kind of success, we need a much better understanding of what its members do, how they compete and cooperate with each other, how they interact with their hosts (that’s us), and how they fare when transplanted in a new host. These are complex questions, which we are only just beginning to answer.
* The article originally intimated that Seres’ Phase 2 trial was the first double-blinded, randomized, placebo-controlled trial for fecal transplants, when there have been others.