Background: Patients with malignancies are at increased risk for recurrent Clostridioides difficile infection (rCDI) due to their immunosuppressed state and frequent exposure to antibiotics and chemotherapy. These factors disrupt the gut microbiome creating an environment conducive to C. difficile colonization. Patients with cancer have higher rates of rCDI and worse outcomes than those without malignancy. SER-109, an investigational microbiome therapeutic, was superior to placebo in reducing rCDI at 8 weeks compared with placebo (12% vs 40%, respectively) in ECOSPOR III, a Phase 3 randomized, double-blind trial of subjects with a history of rCDI [NEJM 2022; 386:220-9]. Here, we report secondary endpoints of rCDI rates at 4, 12 and 24 weeks. Methods: Adults with rCDI (≥3 episodes in 12 months) were screened at 56 US/Canadian sites. After standard-of-care antibiotics (vancomycin or fidaxomicin per investigator discretion), subjects were randomized 1:1 to SER-109 (4 capsules x 3 days) or matching placebo. The primary endpoint was rCDI (recurrent toxin + diarrhea requiring treatment) at 8 weeks; secondary endpoints included rCDI at 4, 12 and 24 weeks. Safety was evaluated through week 24. Results: 281 subjects were screened and 182 (intention-to-treat population; ITT) were randomized (59.9% female; mean age 65.5 years). The most common comorbidities were respiratory disease (36.3%) and cardiovascular disease (32.4%). A total of 28.6% and 18.1% had a history of immunocompromise and malignancy, respectively. Significantly fewer SER-109 vs. placebo treated subjects had rCDI posttreatment compared with placebo recipients at Weeks 4, 8, 12 and 24 (Table). The absolute risk reduction between placebo and SER-109 arms ranged from 22.1% to 28.3% across the 4 timepoints. The safety profile of SER-109 through week 24 was comparable to placebo. Most adverse events (AEs) were mild to moderate gastrointestinal occurrences. More placebo-treated vs SER-109-treated subjects experienced serious AEs through week 8, while comparable proportions of subjects in both arms reported serious AEs from 8 through 24 weeks. Conclusions: In this population of subjects with comorbidities, including malignancy and immunosuppression, SER-109 significantly reduced rCDI rates through week 24 with an observed safety profile comparable to placebo. Clinical trial information: NCT03183128.

*Week 8 was the primary efficacy endpoint. Weeks 4, 12 and 24 were secondary efficacy endpoints.