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Oral drug made from human feces has successfully passed clinical trials, or will be available in United States soon.
Fecal microbiota transplantation (FMT) does offer a proven solution, albeit nauseating, for those battling repeated diarrhea-causing C. difficile infections.
Feces from healthy donors, often delivered to recipients by colonoscopy, can help restore a balanced gut microbiome to eliminate potentially fatal infections.
Several companies are eager to achieve the same effect with less invasive, more standardized treatments, which could be approved by U.S. regulators.
One option is a pill containing bacterial spores isolated from human feces, which has now successfully undergone Phase 3 clinical trials, paving the way for the first approval of such a drug.
FMT can break the cycle of recurrent C. difficile infections, which are common in older patients with other health problems and often begin when antibiotics deplete their normal gut microbiome.
FMT has been part of mainstream medicine for about 10 years, said Sahil Khanna, a Mayo Clinic gastroenterologist who participated in previous clinical trials of SER-109. But graft material from volunteer guts is difficult to standardize.
In some recent cases, inadequately screened donor stool has spread harmful new infections to patients. In 2019, in a clinical trial unrelated to C. difficile, an immune-compromised man died after receiving stool containing antibiotic-resistant E. coli (NEJM, 2019, doi:10.1056/NEJMoa1910437). COVID-19 exacerbates safety concerns: The potential for FMT to transmit SARS-CoV-2 prompted the U.S. Food and Drug Administration (FDA) to issue new warnings and updated donor screening requirements in 2020.
Kelly said, “I think we’ve made it as safe as possible. Even in severely immunocompromised patients, infection transmission doesn’t seem to be a very common problem.” But she said stricter FDA guidance Guidelines have made donor screening more difficult at some medical centers. In the United States, reliable sources of needed fecal preparations are drying up.
The nonprofit fecal bank OpenBiome, the largest U.S. supplier, said in February 2021 that it was gradually reducing production due to financial difficulties and the impending approval of an alternative to FMT.
Clostridium difficile, image via emergency-live.com.
The new pill, called SER-109, made by Seres Therapeutics (hereafter called Seres), is extracted from human feces and purified to reduce resident microorganisms. Feces from pre-screened donors are treated with ethanol, which kills many viruses, fungi and “reproductive” bacteria, that is, bacteria that are in a state of growth and reproduction. The bacteria left behind can form sturdy, thick-walled structures called spores, many from the common phylum Firmicutes.
Seres chief medical officer Lisa von Moltke said this group of bacteria is valuable because they can compete with C. difficile in the gut “to occupy its space, food and carbon source.” Firmicutes also alters the composition of bile acids in the gut, making the gut environment unsuitable for C. difficile, she noted.
Seres’ purification process is designed to remove most pathogens known to pose safety risks to patients, said Vincent Young, a microbiologist and infectious disease physician at the University of Michigan, Ann Arbor, who was not involved in the new clinical trial. “There are no data published yet, but there is reason to believe that [SER-109] is safer than feces.”
In 2016, Seres announced that its treatment failed to show a greater benefit than a placebo in a phase 2 clinical trial. The company’s researchers later concluded that the doses given were too low, and that the C. difficile test used to screen participants may have selected some people who did not have truly recurrent infections (Clinical Infectious Diseases, 2021, doi:10.1093/cid /ciaa387).
The Phase 3 clinical trial, using a higher dose and more precise screening test, included 182 C. difficile-infected participants who were randomized to receive SER-109 or a placebo after a standard course of antibiotics. Of these, 149 completed the 8-week follow-up for this clinical study.
The researchers reported that 40% of the placebo group experienced a recurrence of C. difficile infection, but only 12% of the treatment group experienced a recurrence.
The results of the study were published in the January 20, 2022 issue of the NEJM journal with the title “SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection”.
These results are comparable to those observed with FMT, Kelly said. Many patients want to avoid the discomfort of colonoscopies, and if they have a pill, they choose to take it, she said. (She noted that while the “full spectrum” fecal microbiota can also be taken orally, there are few suppliers of such pills in the United States.)
Some scientists doubt that the new therapy can match the potency of the full fecal microbiome. “That’s a very high bar set by nature,” says Alexander Khoruts, a gastroenterologist at the University of Minnesota-Twin Cities.
He points out that fecal components removed during Seres’ purification process include germ-killing viruses called bacteriophages. , may be important to the success of FMT. “I’m happy that Firmicutes alone … is better than a placebo, but I don’t necessarily believe the other ingredients are negligible,” he said.
Young sees SER-109 as a “good bridge” from FMT to more tailored therapies, and he hopes that as scientists better analyze a patient’s gut microbiome and figure out what kinds of microbes they need Personalized therapy will emerge.
Seres aims to provide the FDA with an application for approval of SER-109 by mid-2022, von Moltke said. Several competitors followed. Microbiome company Rebiotix last year announced positive results from a Phase 3 clinical trial of its relapsing C. difficile therapy, a filtered stool product delivered as an enema.
In October 2021, OpenBiome spin-off Finch Therapeutics announced success in a Phase 2 clinical trial of its product, a pill containing freeze-dried stool.
Vedanta Biosciences has completed a Phase 2 clinical trial of a C. difficile therapy consisting of eight individually selected bacterial strains grown in cell banks rather than isolated from feces.
With the advent of alternatives to FMT, “I don’t want to see the fecal bank model disappear completely,” Kelly said. She noted that intact stool remains important for research to develop treatments for other diseases, such as inflammatory bowel disease.
However, she is eager to see SER-109 rolled out to C. difficile patients. “I think everyone is very happy to have something that’s safe and readily available. Hopefully it’s not too expensive,” she said.
1.Pill derived from human feces treats recurrent gut infections https://www.science.org/content/article/pill-derived-human-feces-treats-recurrent-gut-infections 2.Paul Feuerstadt et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. NEJM, 2022, doi:10.1056/NEJMoa2106516.
Oral drug made from human feces has successfully passed clinical trials
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