• Paul Feuerstadt, Thomas J Louie, Bret Lashner, WangElaine E LEELFrom Yale University School of Medicine, New Haven, and PACT Gastroenterology Center, Hamden - both in Connecticut (P.F.); the University of Calgary and Foothills Medical Centre, Calgary, AB, Canada (T.J.L.); Cleveland Clinic, Cleveland (, Liyang Diao, Jessica A Bryant, Matthew Sims, Colleen S Kraft, Stuart H Cohen, Charles S Berenson, Louis Y Korman, Christopher B Ford, Kevin D Litcofsky, Mary-Jane Lombardo, Jennifer R Wortman, Henry Wu, John G Auniņš, Christopher W J McChalicher, Jonathan A Winkler, Barbara H McGovern, Michele Trucksis, Matthew R Henn, and Lisa von Moltke.
• From Yale University School of Medicine, New Haven, and PACT Gastroenterology Center, Hamden - both in Connecticut (P.F.); the University of Calgary and Foothills Medical Centre, Calgary, AB, Canada (T.J.L.); Cleveland Clinic, Cleveland (B.L.); Seres Therapeutics, Cambridge, MA (E.E.L.W., L.D., J.A.B., C.B.F., M.-J.L., K.D.L., J.R.W., H.W., J.G.A., C.W.J.M., J.A.W., B.H.M., M.T., M.R.H., L.M.); Beaumont Hospital, Royal Oak, Royal Oak, and Oakland University William Beaumont School of Medicine, Rochester - both in Michigan (M.S.); Emory University, Atlanta (C.S.K.); the University of California, Davis, Davis (S.H.C.); the University at Buffalo and Veterans Affairs Western New York Healthcare System - both in Buffalo (C.S.B.); and Capital Digestive Care, Washington, DC (L.Y.K.).
• N. Engl. J. Med. 2022 Jan 20; 386 (3): 220-229.

BackgroundCurrent therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection.MethodsWe conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed.ResultsAmong the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination.ConclusionsIn patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).Copyright © 2022 Massachusetts Medical Society.

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