Safety and Efficacy of Fecal Microbiota Spores, Live-brpk (Formerly SER-109) in Older Patients With Recurrent <italic>Clostridioides difficile</italic> Infection: Findings From an Integrated Analysis of Phase 3 Trials

Background: Older adults are at greater risk for recurrent Clostridioides difficile infection (rCDI) than younger adults. In addition to microbiome changes associated with advanced age, risk factors may include number of comorbidities, reduced immune status, and increased antibiotic exposure. Antibiotics are necessary for rCDI treatment, yet often insufficient to prevent recurrence because they have no effect on C. difficile spores, which germinate in a disrupted microbiome. Fecal microbiota spores, live-brpk (VOWST™; formerly SER-109 and hereafter referred to as VOS for Vowst Oral Spores) is an oral microbiota-based therapeutic to prevent rCDI in adults with rCDI by enabling rapid restoration of the microbiome. In the Phase 3 ECOSPOR III trial, rCDI recurrence risk was lower in patients aged ≥65 years receiving VOS after standard-of-care antibiotics (17%) versus those receiving antibiotics only (46%; RR, 0.36; 95% CI, 0.18–0.72). Herein, we present an integrated analysis of two Phase 3 trials and further describe efficacy/safety in older adults receiving VOS. Methods: ECOSPOR III (randomized, controlled) enrolled 182 patients with ≥2 CDI recurrences; ECOSPOR IV (open-label, single-arm) enrolled 263 patients with rCDI. VOS was administered as 4 capsules over 3 consecutive days following antibiotic treatment. Treatment-emergent adverse events (TEAEs) were collected through Week 8 following VOS therapy; serious TEAEs/AEs of special interest were collected through Week 24. Efficacy endpoints were rCDI (toxin-positive diarrhea requiring treatment) through Weeks 8 and 24. Integrated safety and efficacy data for the overall population and those aged ≥65 years are reported. Results: A total of 349 patients received ≥1 dose of VOS. Through Week 24, 63% of patients (n=221) experienced TEAEs that were mostly mild to moderate and gastrointestinal. TEAEs in ≥10% of patients were flatulence (24%), diarrhea (23%), fatigue (19%), abdominal pain (18%), abdominal distension (17%), nausea (10%), and constipation (10%). No serious TEAEs or deaths were considered related to VOS by investigators; no study withdrawals were due to treatment-related TEAEs. In patients aged ≥65 years (N=183), rates of these outcomes were similar. TEAEs occurred in 64% (n=118) of patients. TEAEs in ≥10% of patients were diarrhea (23%), flatulence (22%), fatigue (18%), abdominal pain (16%), abdominal distension (15%), and constipation (11%). In the overall population, 33 patients (9.5%; 95% CI, 6.6–13.0) experienced on-study recurrence through Week 8 and 53 (15.2%; 95% CI, 11.6–19.4) experienced on-study recurrence through Week 24. At Weeks 8 and 24, 90.5% (95% CI, 87.0–93.4) and 84.8% (95% CI, 80.6–88.4) of patients in the overall population, respectively, were recurrence free. In patients aged ≥65 years, rCDI rate through Week 8 was 14.2% (95% CI, 9.5–20.1). Conclusions: This integrated analysis confirms VOS was well tolerated and rCDI rates were low, supporting early/rapid microbiome restoration in preventing rCDI. In patients ≥65 years, no clinically important differences in the safety profile of VOS were observed versus that in the overall patient population; efficacy outcomes in older patients were consistent with those in the overall population. These cross-trial observations suggest rCDI management with VOS may be considered in a vulnerable elderly population at high risk for recurrent disease.