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By the University at Buffalo
People who develop colitis with the virulent bacterium C. difficile, usually after a course of antibiotics or chemotherapy, experience severe diarrhea, inflammation of the colon and abdominal pain. Each year, nearly half a million Americans suffer from it. About 1 in 6 will go on to experience a relapse, and sometimes it continues to recur. C. difficile infections (CDI) are responsible for approximately 20,000 deaths annually.
So, when patients at the VA Western New York Healthcare System who are prone to recurrences of CDI were invited to participate in a clinical trial conducted at the VA with a drug that might prevent relapse, many were interested.
“Most were elated to know they might get something that could prevent a fourth recurrence,” said Charles Berenson, M.D., associate professor in the department of medicine in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo. Berenson, who is also a member of the Infectious Diseases division at the VA, is a co-author on the paper reporting on the success of the trial published in January in the New England Journal of Medicine. Barbara H. McGovern, M.D., vice president for medical affairs at Seres Therapeutics, is senior author.
The findings, based on the study of 182 participants, including six who completed the study at the Buffalo VA, revealed that this specific microbiome therapy successfully prevents C. difficile recurrences in people prone to relapse. Seres Therapeutics is now seeking Food and Drug Administration approval for the therapy.
Restoring the Microbiome
“I think this is definitely going to change how we treat CDI relapses,” said Berenson, a member of the division of infectious diseases at UB and a physician with UBMD Internal Medicine. “What has been missing is something that will restore their microbiome, and that’s what this study establishes.”
After a CDI diagnosis, patients receive specific antibiotics for CDI. “But for patients prone to relapse, they need more than the CDI treatment; they need restoration of the microbiome of the colon. That’s what this paper focuses on.”
While the antibiotics will kill the vegetative form of the CDI, there is a more insidious, sporulated form that Berenson says “lays low” and then flares again as soon as the antibiotic therapy stops; that’s what causes relapse.
To qualify for the study, patients had to have had a third recurrence of CDI.
“Most were very happy to participate, even though they couldn’t know if they were getting a placebo or a real drug,” Berenson said. Patients who received placebo and experienced a recurrence could receive the medication in an open label arm while the trial was ongoing.
The therapy consists of a type of bacteria called firmicutes that are part of normal colonic flora. Scientists have been interested in firmicutes because these bacteria show up soon after a fecal transplant, which until now has been an extremely successful treatment for recurrent CDI.
But while fecal transplants have been successful, they require either a colonoscopy or a naso-gastric/duodenal tube and can, in rare cases, transmit other dangerous bacteria to patients. The emergence of SARS-CoV2 added another layer of complexity to doing fecal transplants.
By contrast, the firmicutes treatment developed by Seres Therapeutics, called SER 109, is taken orally. After patients are treated for the acute recurrence with standard-of-care antibiotics, they are given four capsules daily of SER 109 for three days.
Berenson, who considers himself primarily a bench scientist and clinician, said his motivation to participate in the study was the quality of the scientific data on which it was based.
‘Tremendous Scientific Benefit’
“I’ve been here a long time doing bench research,” he said. “I’ve always been interested in clinical trials, but much of the time the need did not seem overwhelming, and the underlying science was limited. I had never participated in a clinical study in concert with industry, but when I read their data from the phase two trial and from their interest in exploring basic underlying mechanisms, I thought this could have tremendous scientific benefit and great potential for people with relapses. The results are very compelling and made this a very rewarding experience.”
A key factor in the science behind why SER 109 works is what’s happening in the microbiome of these patients.
“People prone to C. difficile relapse have a different microbiome than people who don’t have C. difficile,” Berenson said.
Firmicutes spores populate the colons of people with a healthy microbiome. SER 109 changes their microbiome to a healthier state so that they are better able to resist CDI.
“The data indicate that the firmicutes bacteria successfully engraft and have intrinsic enzymes that change the environment that the C. diff lives in, making it less hospitable to C. diff,” Berenson said. “I treat people with C. diff all the time, but this research changed my understanding of how the disease evolves.”
Other co-authors are from institutions including Yale, the University of Calgary, Cleveland Clinic, Emory University and the University of California, Davis.