1953. VE303, a Rationally Designed Bacterial Consortium for Prevention of Recurrent Clostridioides difficile (C. Difficile) infection (rCDI), Stably Restores the Gut Microbiota After Vancomycin (vanco)-Induced Dysbiosis in Adult Healthy Volunteers (HV)

BACKGROUND: Gut microbiota alterations and resulting changes in metabolites involved in colonization resistance and host responses, including bile acids (BA) and short-chain fatty acids (SCFA), are hallmarks of C. difficile infection. Reduction in rCDI was shown with fecal microbiota transplants (FMT), but FMT has limitations for routine use and carries unforeseen risks. VE303 is a first-in-class drug being developed for prevention of rCDI consisting of a rationally defined bacterial consortium manufactured under GMP conditions. VE303 comprises 8 distinct species belonging to Clostridium clusters IV, XIVa, and XVII, the commensal bacteria associated with clinical response in FMT, suppress C. difficile growth in vitro and improve survival in vivo. METHODS: A first-in-human Phase 1 dose-escalation study assessed safety and tolerability of VE303 in HV after vanco-induced dysbiosis. PK (strain colonization and durability) and PD (restoration of the resident microbiota, SCFA pool, and BA pool) were evaluated by metagenomic sequencing and metabolomics analysis of fecal material. RESULTS: HV (N = 23) received oral vanco 125 mg QID for 5 days followed by VE303 capsules at escalating single then multiple doses (total dose range 1.6 × 10(9) to 1.1 × 10(11) CFU). VE303-related AEs, mostly gastrointestinal, all Grade 1 and transient, were observed in 35% of HV. Colonization with VE303 strains was abundant, durable (detected at 24 weeks), and dose-dependent. VE303 rapidly expanded 10- to 100-fold and each strain was detectable within 2 days after dosing. VE303 enhanced subjects’ microbiota and metabolic recovery after vanco treatment. When compared with the vanco-only cohort (N = 5), VE303 led to earlier and more complete recovery of beneficial taxa (eg, Bacteroidetes, Firmicutes), reduction in inflammatory taxa (e.g., Proteobacteria) (Figure 1.), and recovery of the secondary BA and SCFA pools. CONCLUSION: VE303, a rationally designed microbial consortium, was safe, well tolerated, and efficiently restored microbiome composition after antibiotic-induced dysbiosis in a dose-dependent manner. VE303 was associated with early recovery of key PD markers of response, including microbiota composition, bile acid, and SCFA pools. A Phase 2 study of VE303 for prevention of rCDI is underway (NCT03788434). [Image: see text] DISCLOSURES: All Authors: No reported Disclosures.