DURABILITY OF THE CLINICAL RESPONSE TO SER-109, AN INVESTIGATIONAL ORAL MICROBIOME THERAPEUTIC, IN A PHASE 3 OPEN-LABEL TRIAL (ECOSPOR IV) IN PATIENTS WITH RECURRENT <i>CLOSTRIDIOIDES DIFFICILE</i> INFECTION

Background: Recurrent Clostridioides difficile infection (rCDI) is a debilitating disease associated with significant healthcare burden and low quality of life. The greatest risk factor for rCDI is a history of recurrence, although older age (≥65 years) and comorbidities also increase risk. Recurrent CDI occurs in 20-36% of patients with 1st recurrence and ≥40% in those with ≥2 recurrences. In a Phase 3 randomized controlled trial (ECOSPOR III), the investigational oral microbiome therapeutic SER-109 was superior to placebo in reducing risk of rCDI at 8 weeks in patients with ≥2 recurrences (12% vs 40%) and this response was durable through 24 weeks [Feuerstadt NEJM 2022; Cohen JAMA 2022]. Here we present safety and efficacy data from a Phase 3 open-label trial (ECOSPOR IV), including durability of response in patients with 1^st and ≥2 recurrences.

Methods: Adults with rCDI were enrolled at 72 North American sites in 2 cohorts: 1) rollover subjects with rCDI in ECOSPOR III, diagnosed by toxin EIA) and 2) subjects with ≥1 CDI recurrence (diagnosed by PCR or toxin EIA, inclusive of the current episode). After standard-of-care antibiotics, subjects received SER-109 (4 capsules daily x 3 days). Efficacy endpoints, including the proportion of subjects with rCDI (toxin+ diarrhea requiring treatment), were evaluated through Week 8; safety and durability of response were assessed through Week 24.

Results: Of 351 subjects screened, 263 were enrolled (Cohort 1: N=29; Cohort 2: N=234; 68% female; mean age 64 years). Approximately 1/3 of subjects enrolled with their 1st recurrence. Comorbidities included cardiac disorders (31%), neoplasms (21%), Type 2 diabetes (11%), COPD (10%), chronic kidney disease (9%), and hepatobiliary disorders (9%). Overall, 141 subjects (54%) had treatment-emergent adverse events (TEAEs), the majority of which were mild to moderate and gastrointestinal. There were 8 deaths (3%) and 33 subjects (13%) with serious TEAEs; none were treatment-related (Table 1).

Overall, 240 subjects (91.3%) had clinical response (ie, no CDI recurrence) at 8 weeks. Of these, 227 subjects (94.6%) maintained a durable response through Week 24. Among the 240 responders at Week 8, 72 subjects (30%) had a history of 1st recurrence; the remainder had a history of ≥2 CDI recurrences. The proportion of Week 8 responders who maintained durable response through Week 24 was similar between those with a history of 1st recurrence vs ≥2 recurrences (94.4% vs 94.6%, respectively; Figure 1).

Conclusions: SER-109, a potential first-in-class oral investigational microbiome therapeutic, was well-tolerated in this population of patients with multiple comorbidities. High and durable clinical response rates were observed through Week 24, regardless of the number of prior CDI recurrences, supporting the potential benefit of microbiome repair following antibiotics to treat rCDI.