An oral treatment with freeze-dried human stool can successfully treat Clostridioides difficile infections by increasing the diversity of microorganisms in the colon, researchers say.
CP101, under development by Finch Therapeutics, proved more effective than a placebo in preventing recurrent infections for up to 24 weeks.
The CP101 capsules contain a powder of freeze-dried human stools from screened donors. They restore natural diversity that has been disrupted by antibiotics, said Jessica Allegretti, MD, MPH a gastroenterologist at Brigham and Women’s Hospital in Boston, Massachusetts.
The treatment offers an alternative to fecal microbiota transplant, which can effectively treat antibiotic-resistant C difficile infections but is difficult to standardize and administer — and doesn’t have full approval from the US Food and Drug Administration, she added.
“I think this marks a moment in this space where we’re going to have better, safer, and more available options for patients,” she told Medscape Medical News. “It’s exciting.”
Allegretti is an author on three presentations of results from PRISM3, a phase 2 trial of CP101. They will be presented this week at the American College of Gastroenterology 2021 annual meeting in Las Vegas (also being held virtually). These results extend out to 24 weeks, whereas the 8-week results of this trial were presented a year ago at the same meeting.
The study enrolled 198 people who received antibiotics for recurrent C difficile infections. Some patients had two or more recurrences, while others had only one recurrence but were 65 years of age or older.
“That was a unique aspect of this study, to see the effect of bringing a therapy like CP101 earlier in the treatment paradigm,” said Allegretti. “You can imagine for an older, frail, or more fragile patient that you would want to get rid of this [infection] earlier.”
After waiting 2-6 days for the antibiotics to wash out, the researchers randomly assigned 102 of these patients to take the CP101 pills orally and 96 to take placebo pills, both without bowel preparation.
The two groups were not significantly different in age, gender, comorbidities, the number of C difficile recurrences, or the type of test used to diagnose the infection (PCR-based vs toxin EIA-based.)
After 8 weeks, 74.5% of those given the CP101 pills had not had a recurrence, compared with 61.5% of those given the placebo. The difference was just barely statistically significant (P = .0488).
Sixteen weeks later, the effect endured, with 73.5% of the CP101 group and 59.4% of the placebo group still free of recurrence. The statistical significance of the difference improved slightly (P = .0347).
Drug-related emergent adverse events were similar between the two groups: 16.3% for the CP101 group vs. 19.2% for the placebo group. These were mostly gastrointestinal symptoms, and none were serious.
Some of the patients received vancomycin as a first-line treatment for C difficile infections, and the researchers wondered if the washout period was not sufficient to purge that antibiotic, leaving enough to interfere with the effectiveness of CP101.
Therefore, they separately analyzed 40 patients treated with fidaxomicin, which they expected to wash out more quickly. Among these patients, 81% who received CP101 were free of recurrences, at 8 weeks and 24 weeks. This compared with 42.1% of those who received the placebo, at both timepoints. This difference was more statistically significant (P = .0211).
Understanding How It Works
To understand better how CP101 achieves its effects, the researchers collected stool samples from the patients and counted the number of different kinds organisms in each sample.
At baseline, the patients had about the same number, but after a week the diversity was greater in the patients treated with CP101, and that difference had increased at week 8. The researchers also found much less diversity of organisms in the stools of those patients who had recurrences of C difficile infection.
The diversity of microbes in the successfully treated patients appeared to have been introduced by CP101. Allegretti and colleagues measured the number of organisms in the stool samples that came from CP101. They found that 96% of patients colonized by the CP101 organisms had avoided recurrence of the C difficile infections, compared with 54.2% of those patients not colonized by these microbes.
“We now have some microbiome-based markers that show us as early as week 1 that the patient is going to be cured or not,” Allegretti said.
Based on these results, Finch plans to launch a phase 3 trial soon, she said.
The data on colonization is interesting because it has not been found with fecal microbiota transplants, said Purna Kashyap, MBBS, co-director of the Microbiome Program at the Mayo Clinic College of Medicine in Rochester, Minnesota, who was not involved in the study.
But to better interpret the data, it would be helpful to know more about how the placebo and CP101 groups compared at baseline with regard to medications, immunosuppression, and antibiotics used to treat the C difficile infections, Kashyap said. He was struck by the lower cure rate in the portion of the placebo group treated with fidaxomicin.
“Overall, I think these are exciting observations based on the data but require careful review of the entire data to make sense of [them], which will happen when it goes through peer review,” he told Medscape Medical News in an email.
Several other standardized microbiota restoration products are under development, as reported by Medscape Medical News, including at least two other capsules. In contrast to CP101, which is made up of whole stool, VE303 (Vedanta Biosciences) is a “rationally defined bacterial consortium,” and SER-109 (Seres Therapeutics) is a “consortium of highly purified Firmicutes spores.” VE303 has completed a phase 2 trial, and SER-109 has completed a phase 3 trial.
Allegretti is a consultant for Finch Therapeutics, which funded the trial. Kashyap has disclosed no relevant financial relationships.
American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting: Abstracts P0129 and P0130 presented October 24, 2021, and Abstract 25 to be presented October 26, 2021.
Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio, and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at lairdharrison.com or follow him on Twitter@LairdH