麻豆传媒

An investigational oral microbiome therapeutic, SER-109, stopped repeat Clostridioides difficile (C. diff) infections in outpatients whose symptoms had initially resolved with standard antibiotics, a phase III trial found.

In an intention-to-treat analysis of 182 patients, recurrence rates for those who received SER-109 were significantly lower compared to those receiving placebo (12% vs 40%, respectively; relative risk [RR] 0.32, 95% CI 0.18-0.58, P<0.001), reported Barbara McGovern, MD, of Seres Therapeutics in Cambridge, Massachusetts, and colleagues.

The number needed to treat to avoid one C. diff recurrence was 3.6, the authors wrote in the.

Reductions in recurrence for the SER-109 group held up in age-stratified analyses as well:

• Under 65: RR 0.24 (95% CI 0.07-0.78)
• 65 and up: RR 0.36 (95% CI 0.18-0.72)

Safety was comparable to placebo, with no serious adverse events related to the treatment, McGovern's group noted.

"Recurrence of C. difficile infection is an important problem, since over 20% of patients with an initial infection develop recurrences," co-author Bret Lashner, MD, of the Cleveland Clinic in Ohio, told 麻豆传媒. "Even though oral vancomycin and fidaxomicin can treat the C. difficile infection, recurrence occurs due to dysbiosis," and SER-109 improves dysbiosis, Lashner explained.

These antibiotics do not kill C. diff spores, and "antibiotic-induced loss of beneficial Firmicutes bacteria" can enable "C. diff spore germination and a cycle of recurrent disease," the researchers explained.

"A durable clinical response is dependent on the resilience of the microbiome -- that is, the recovery of these beneficial resident bacteria after discontinuation of antibiotic treatment," wrote McGovern and co-authors. "Antibiotics are necessary but not sufficient to achieve a sustained clinical response, thus highlighting the need for a two-pronged treatment approach that includes microbiome repair."

SER-109, containing 3 × 10⁷ spore colony-forming units of purified Firmicutes spores, was developed to treat recurrent C. diff infections. Data from the so-called trial were previously presented at last year's Digestive Disease Week.

"This study is an important addition to the evolving field of microbiome therapeutics," said Brian B. Baggott, MD, also of the Cleveland Clinic in Ohio, who was not involved in this research.

The phase III study took place at 56 sites in the U.S. and Canada from July 2017 to September 2020. It consisted of 182 adults randomized 1:1 to receive four daily capsules of SER-109 (n=89) or placebo (n=93) for 3 days.

Participants had recurrent C. diff, evidenced by at least three infections (including an acute qualifying episode) within 12 months, a positive C. diff toxin test and resolution of symptoms while receiving 10 to 21 days of antibiotics. They were stratified by age and antibiotics received. Patients were monitored for 8 weeks for recurrence, and adverse events were assessed at weeks 2 and 8.

The primary efficacy objective was superiority of SER-109 over placebo in reducing recurrent C. diff infection up to 8 weeks after therapy.

Mean age of patients was 66 years, and 93% were white. Women made up a higher proportion of patients in the SER-109 versus placebo group (67% vs 53%). A little under three-fourths of both groups received vancomycin and the rest received fidaxomicin. Overall, 149 of 182 patients completed 8 weeks of follow-up (82%).

Subgroup analyses confirmed less frequent C. diff recurrence, regardless of if patients received vancomycin (RR 0.41, 95% CI 0.22-0.79) or fidaxomicin (RR 0.09, 95% CI 0.01-0.63).

Treatment-related adverse events occurred in about half of patients in both groups. A large majority of patients in both groups reported gastrointestinal disorders (87-88%), with flatulence the most common (70-76%). In addition, 63-71% of patients reported general disorders and administration site conditions, with 59-63% reporting fatigue.

Three patients in the SER-109 group died, unrelated to treatment.

The group noted limitations to the data. The study sample lacked diversity and stool samples were not obtained prior to initiating antibiotics, so there was a lack of data on the "pre-antibiotic microbiome."

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