IMAGE: BIOMEDICAL IMAGING UNIT/SOUTHAMPTON GENERAL HOSPITAL/SCIENCE SOURCE
SCIENCE science.org 28 JANUARY 2022 • VOL 375 ISSUE 6579 369in previous trials of SER-109. In a few re-
cent cases, inadequately screened donor
stool has transmitted other potentially
deadly pathogens to C. difficile patients.
COVID-19 has heightened safety concerns:
The possibility that introducing fecal mat-
ter might transmit SARS-CoV-2 prompted
new donor screening requirements from
the U.S. Food and Drug Administration
(FDA) in 2020. (The agency classifies the
fecal microbiota used in transplants as an
investigational drug, but doesn’t require
that it go through the formal approval pro-
cess for clinical use.)
“I think we’ve made it as safe as it can
possibly be,” Kelly says of traditional FMT.
She leads a registry tracking hundreds of
people who have received the procedure.
“Transmission of infection just doesn’t
seem to be a very common problem, even
in highly immunocompromised patients,”
she notes.
Yet stricter FDA guidelines have made
donor screening harder for some medi-
cal centers, Kelly says. And the largest
U.S. provider of feces for transplant, the
nonprofit stool bank OpenBiome, an-
nounced in February 2021 it was wind-
ing down production, citing financial
struggles and the coming approval of
FMT alternatives.
Seres Therapeutics hopes its product,
SER-109, will be one of those. The pill is
made by treating stool from prescreened
donors with ethanol, which kills many
viruses, fungi, and “vegetative” bacteria—
those in a state of growth and reproduc-
tion. Left behind are bacteria that can form
hearty, thick-walled spores, many of them
from the common phylum Firmicutes. Bac-
teria in this group are valuable because
they can compete with C. difficile in the
gut and discourage its growth by changing
the composition of bile acids, says Seres
Chief Medical Officer Lisa von Moltke.
Seres’s purification process should get
rid of most pathogens known to pose
safety risks to recipients, says Vincent
Young, a microbiologist and infectious dis-
ease physician at the University of Michi-
gan, Ann Arbor, who has no connection to
the company or the new trial. Although it
hasn’t been proved yet, he says, “there are
reasons to think that [SER-109] is safer
than feces.”
Seres’s phase 3 trial included 182 par-
ticipants with recurrent 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. The infection re-
turned in 40% of the placebo group, but in
just 12% of the treatment group, research-
ers reported last week in The New Eng-land Journal of Medicine. Those results
are comparable to results seen with FMT,
Kelly says.
Seres has competitors. 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, and
has filed for FDA approval. Finch Thera-
peutics, a spinoff of OpenBiome, declared
success last year in a phase 2 trial of its
product, a pill that contains
freeze-dried stool. And Ve-
danta Biosciences has com-
pleted a phase 2 trial of an
oral C. difficile therapy con-
sisting of eight individually
selected bacteria strains
grown in cell banks rather
than isolated from stool.
Many patients want to
avoid the discomfort of
colonoscopies, and will opt
for a pill if it’s available,
Kelly says. (Although “full-
spectrum” fecal microbiota
can also be delivered orally,
there are few providers of
such pills in the United States, she notes.)
How the European Commission will regu-
late newly developed pills or other fecal
microbiota products remains uncertain,
says Josbert Keller, a gastroenterologist
at Leiden University Medical Center and
founder of the Netherlands Donor Feces
Bank. But he expects more standardized
products are likely to replace whole feces–
based products that banks like his currently
supply—“and I think that should be the
aim,” he says.
Other researchers are skeptical that newmicrobiome therapies like SER-109 can
match the potency of the complete fe-
cal microbiota. “It’s a really high stan-
dard that nature has established,” says
Alexander Khoruts, a gastroenterologist at
the University of Minnesota, Twin Cities,
who developed some of the technology be-
hind Finch’s pill.
He notes that components of feces re-
moved during Seres’s purification process, in-
cluding bacteria-killing viruses called phages,
might be important to the
success of FMT. “I’m grati-
fied that Firmicutes alone
... is better than placebo,” he
says, “but I’m not necessar-
ily convinced that the other
components are dismissible.”
Young, who has con-
sulted for Vedanta, sees
SER-109 as “a good bridge”
from FMT to more tailored
therapies, which he hopes
will emerge as researchers
get better at determining
which microbial species
each patient needs.
Kelly stresses that stool
banks remain important sources of whole
feces for research, as other conditions
such as inflammatory bowel disease may
require different collections of microbes
than those provided by C. difficile treat-
ments on the horizon. “I would hate to
see the stool bank model disappear com-
pletely,” she says.
Still, she’s eager to see SER-109 rolled
out to C. difficile patients. “I think ev-
erybody is very happy to have something
that’s safe and readily available,” she says.
“Let’s hope it’s not too expensive.” jA microbiome-altering pill
cleared recurrent infections
with the potentially deadly
bacterium Clostridium difficile.“Everybody is very
happy to
have something
that’s safe and
readily available.
Let’s hope it’s
not too expensive.”
Colleen Kelly,
Brown University