S364 Efficacy and Safety of Investigational Therapeutic Microbiome SER-109 in Recurrent Clostridioides difficile Infection: A Systematic Review

Introduction: Current therapies for recurrent Clostridioides difficile infection (CDI) often fail to address the disrupted microbiome contributing to C. difficile spore germination and subsequent toxin production. SER-109, an investigational therapeutic microbiome, is composed of purified Firmicutes spores and shows promise in treating recurrent CDI. Our aim was to evaluate the efficacy, safety and recurrence rate of CDI following administration of oral SER-109. Methods: We systematically reviewed available literature on PUBMED using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) for clinical trials involving SER-109. We found 3 clinical trials that met our inclusion criteria and primary efficacy endpoint criteria. For assessing bias, we used the Cochrane Collaboration's tool risk assessment of the clinical trials (Figure 1). Results: Oral SER-109 was well tolerated with the rate of recurrent CDI remaining low, regardless of the number of prior recurrences or patient demographics. The diagnostic approach did not significantly impact the beneficial effect of SER-109. In 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 mild and similar to that of placebo. Our findings are summarized in Table 1. Conclusion: SER-109 holds promise as a safe and effective treatment for recurrent CDI. Further research is warranted to confirm its long-term efficacy and explore potential mechanisms underlying its impact on the disrupted gut microbiome.Figure 1.: Bias analysis of the clinical trials in the systematic review. Table 1. - Characteristics and outcomes of selected studies STUDIES ECOSPORMcGovern BH et al. ECOSPOR IIIFeuerstadt P et al. ESCOPOR IVSims MD et al. Country USA USA & Canada USA & Canada Study Design Phase-2 Multicenter, randomized, double blind, placebo controlled. Phase-3, Multicenter, randomized, double-blind, placebo controlled. Open Label Extension & Open Label Program. Inclusion Criteria Adults above 18 years of age with 3 or more CDI episodes within the past 9 or 12 months. Adults above 18 years of age with 3 or more CDI episodes within the past 9 or 12 months. Cohort 1: CDI recurrence within 8 weeks after treatment or placebo.Cohort 2: new patients above 18 years of age who had one or more CDI episodes and had responded to a course of antibiotic treatment. Patient Demographics Total n=89,Female 60 (67.4%),93.3% White, mean age: not listed. Total n= 182, mean Age 65.5 ± 16.5 years, female 67%93% White, 99% outpatients. Total n=263,Female 180 (68.4%), mean Age 64±15.7 years, 92.4% White. Diagnostic Approach 80.9% diagnosed by PCR19.1% by GDH+/Toxin+. Enzyme immunoassay or enzyme immunoassay and cell cytotoxicity neutralization assay, specific % not listed. Toxin enzyme immunoassay (EIA), polymerase chain reaction (PCR) assay for toxin genes, and cell cytotoxicity neutralization assay.69 patients (26.4% of the enrolled participants) were enrolled based on PCR diagnostics alone. Prior Recurrences 3 (53.9%, n=48); 4 (29.2%, n=26); ≥5 (16.9%, n=15). 3 (55%, n=49); ≥4 (44%, n=39); No Data (1%, n=1). 2 (29.3%, n=77); ≥3 (70.7%, n=186). Previous Antibiotic Regimen Vancomycin (78.7%, n=70), Fidaxomicin (21.3%, n=19). Vancomycin (72%, n=64), Fidaxomicin (28%, n=25). Vancomycin (72.6%, n=191); Fidaxomicin (27.4%, n=72). Number of patients in treatment group 59 89 Cohort 1: 29Cohort 2: 234 Number of patients in control group 30 93 0 Intervention SER-109 vs placebo, oral SER-109 vs placebo, oral SER-109, oral Time of outcome assessment 8 and 24 weeks after treatment. 4,8,12, and up to 24 weeks after initiation of treatment. Cohort 1: up to 8 weeks after treatmentCohort 2: up to 8 and 12 weeks after treatment. Recurrence Rates 44% (n=59) in the SER-109 group vs 53.3% (n=30) in the placebo group developed recurrence at 8 weeks. 12% (n= 11) in SER-109 group vs 40% (n=37) in placebo groupRR 0.32; 95% CI 0.18 to 0.58; P < 0.001 for RR< 1; P < 0.001 for RR < 0.833). By week 24, 13.7%, n=36 patients had CDI recurrence (95% CI, 9.8%-18.4%). Safety Profile 76.7% of SER-109 subjects experienced adverse events (AEs), including 40.0% mild, 26.7% moderate, and 10.0% severe, with 15.0% reporting serious AEs; in the placebo group, 69.0% had AEs, with 37.9% mild, 31.0% moderate, and 10.3% reporting serious AEs. 93% of SER-109 and 91% of placebo recipients reported adverse events, with 51% possibly treatment-related, 8% experiencing serious adverse events in the SER-109 group, and 2% of deaths in the SER-109 group not linked to the drug. 53.6% mild to moderate adverse events, with 6.5% invasive infections, 12.5% serious adverse events, and 3.0% of deaths not linked to SER-109; the most common issues were gastrointestinal symptoms and urinary tract infections. Limitations Lack of certainty in diagnosing all patients accurately. Low representation of minority population and lack of stool specimen before antibiotic treatment. Open-label design, due to this it is challenging to make conclusive statements about the efficacy of SER-109.

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