For people fighting repeat infections of the diarrhea-causing bacterium Clostridium difficile, fecal microbiota transplant (FMT) offers a proven—if unappetizing—solution. Stool from a healthy donor, usually delivered via colonoscopy, can help restore a balanced community of gut microbes to vanquish the potentially deadly infection. Several companies are eager to achieve the same effect with less invasive, more standardized therapies, which could gain U.S. regulatory approval. One option, a pill containing bacterial spores isolated from human feces, has now succeeded in a phase 3 trial, paving the way for the first approval of its kind.
“It’s a step forward for the field, for sure,” says Colleen Kelly, a gastroenterologist at Brown University who was an investigator on an earlier trial of the pill, called SER-109, but was not involved in the new efficacy study. “[For] the majority of patients that we see for recurrent C. diff … [this treatment] might be able to solve the problem.”
FMT can break the cycle of recurrent C. difficile infections, which are common in elderly patients with other health problems, and often start when antibiotics deplete their normal microbiomes. FMT has been part of mainstream medicine for about 10 years, says Sahil Khanna, a gastroenterologist at the Mayo Clinic who has been involved in previous trials of SER-109. But the transplant material, which comes from the bowels of volunteers, is hard to standardize.
In a few recent cases, inadequately screened donor stool has transmitted harmful new infections to patients. In 2019, a man with a compromised immune system died after receiving stool containing antibiotic-resistant Escherichia coli bacteria in a clinical trial unrelated to C. difficile. And COVID-19 has heightened safety concerns: The possibility that FMT might transmit SARS-CoV-2 prompted a new warning and updated donor screening requirements from the U.S. Food and Drug Administration (FDA) in 2020.
“I think we’ve made it as safe as it can possibly be,” says Kelly, who leads a registry tracking hundreds of patients after the procedure. “Transmission of infection just doesn’t seem to be a very common problem, even in highly immunocompromised patients,” she notes. But the stricter FDA guidelines have made donor screening harder for some medical centers, she says. And in the United States, reliable sources of the required stool preparations are drying up. The largest U.S. provider, the nonprofit stool bank OpenBiome, said in February 2021 it was winding down production, citing financial struggles and the coming approval of FMT alternatives.
The new pill, called SER-109 and made by Seres Therapeutics, is derived from human feces purified to winnow down the resident microbes. Stool from prescreened donors is treated with ethanol, which kills many viruses, fungi, and “vegetative” bacteria—those in a state of growth and reproduction. Left behind are bacteria that can form hearty, thick-walled structures called spores, many of them from the common phylum Firmicutes. Bacteria in this group are valuable because they can compete with C. difficile in the gut, “taking its space and its food and its carbon sources,” says Seres Chief Medical Officer Lisa von Moltke; the Firmicutes also change the composition of bile acids in the intestines, making the environment less hospitable for C. difficile, she notes.
Seres’s purification process is designed to get rid of most pathogens known to pose safety risks to patients, says Vincent Young, a microbiologist and infectious disease physician at the University of Michigan, Ann Arbor, who was not involved with the new trial. “There’s no data yet, but there are reasons to think that [SER-109] is safer than feces.”
In 2016, Seres announced its treatment had failed to show greater benefits than a placebo in a phase 2 trial. Company researchers later concluded that the prescribed dose had been too low, and the C. difficile test used to screen participants may have selected for some who didn’t really have recurrent infections.
The phase 3 trial, which used a higher dose and a more precise screening test, included 182 participants infected with C. difficile who were randomized to get either SER-109 or a placebo, following a standard course of antibiotics. Of those, 149 completed the study’s 8-week follow-up. C. difficile infection recurred in 40% of the placebo group, but just 12% of the treatment group, researchers report today in The New England Journal of Medicine.
Those results are comparable to results seen with FMT, Kelly says. Many patients want to avoid the discomfort of colonoscopies, and will opt for a pill if it’s available, she says. (Although “full-spectrum” fecal microbiota can also be delivered orally, there are few providers of such pills in the United States, she notes.)
Other researchers are skeptical that the new therapy can match the potency of the complete fecal microbiota. “It’s a really high standard that nature has established,” says Alexander Khoruts, a gastroenterologist at the University of Minnesota, Twin Cities. He notes that components of feces removed during Seres’s purification process, including bacteria-killing viruses called phages, might be important to the success of FMT. “I’m gratified that Firmicutes alone … is better than placebo,” he says, “but I’m not necessarily convinced that the other components are dismissible.”
Young sees SER-109 as “a good bridge” from FMT to more tailored therapies, which he hopes will emerge as researchers get better at analyzing individual patients’ microbiomes—and figuring out which microbial species they need.
Seres aims to file an application for FDA approval of SER-109 in mid-2022, von Moltke says. And several competitors are close on its heels. The microbiome company Rebiotix Inc. last year announced positive results from a phase 3 trial of its recurrent C. difficile treatment, a filtered stool product delivered as an enema. In October 2021, Finch Therapeutics, a spinoff of OpenBiome, declared success in a phase 2 trial of its product, a pill containing freeze-dried stool. And Vedanta Biosciences has completed a phase 2 trial of a C. difficile therapy consisting of eight individually selected bacteria strains grown in cell banks rather than isolated from stool.
With FMT alternatives on the horizon, “I would hate to see the stool bank model disappear completely,” Kelly says. Whole feces will still be important for research to develop treatments for other conditions such as inflammatory bowel disease, she notes. But she’s eager to see SER-109 rolled out to C. difficile patients. “I think everybody is very happy to have something that’s safe and readily available,” she says. “Let’s hope it’s not too expensive.”