RANDOMIZED, DOUBLE-BLIND, PLACEBO (PBO)-CONTROLLED, SINGLE- AND MULTIPLE-DOSE PHASE 1 STUDY OF VE202, A DEFINED BACTERIAL CONSORTIUM FOR TREATMENT OF IBD: SAFETY AND COLONIZATION DYNAMICS OF A NOVEL LIVE BIOTHERAPEUTIC PRODUCT (LBP) IN HEALTHY ADULTS

Abstract

Abstract IBD patients can have reduced gut commensal abundance, relative expansion of pro-inflammatory taxa, and reduced microbial diversity and short-chain fatty acid production. FMT leads to clinical remission in some UC patients, but is a complex, nonscalable process with inconsistent composition/quality that has led to death from transmission of pathogens undetected in screening. VE202 is a rationally defined LBP of 16 beneficial Clostridia from clusters IV, XIVa, and XVIII, with properties including association with healthy human microbiomes, promotion of colonic Treg cells, production of beneficial and immunoregulatory metabolites, efficacy in mouse colitis models, and lack of overt pathogenic or toxigenic features. These properties could help restore a healthy microbiome in UC patients. Another rationally defined LBP, VE303, showed activity in a Phase 2 study for prevention of recurrentC. difficile. The goal of the current Phase 1 study was to evaluate safety and colonization of VE202, to inform planned Phase 2 trials in UC patients. METHODS: After 5 days of vancomycin pretreatment at 125mg po QID to decrease gut microbial burden, 31 healthy adults received 1 dose at 2 dosage levels (6 VE202, 3 PBO per dosage level) or a 14-day course (9 VE202, 4 PBO) of the lower dose. Each VE202 delayed-release enteric capsule contained ∼1x109 CFU of bacteria. Safety was monitored through Week 12, with phone follow-up at Week 24. Stool was collected for LBP strain detection and exploratory microbiome, metabolomic, and immune markers. RESULTS: VE202 was well tolerated with no dose-dependent pattern of AEs. The only MedDRA organ classes with ≥20% reported AEs in VE202 recipients were: —Single-dose cohorts (N=12): GI (n=6; 50%), nervous system (n=4; 33.3%), investigations and infections/infestations (n=3 each; 25%) —14-day cohort (N=9): GI (n=5; 55.6%), general/administration site, musculoskeletal/connective tissue and nervous system (n=3 each; 33.3%), and skin/subcutaneous tissue (n=2; 22.2%) In VE202 recipients (N=21), the only AEs seen in ≥10% of subjects were abdominal discomfort, diarrhea, headache (n=4 each; 19.0%), and fatigue (n=3; 14.3%). No severe AEs or clinically significant trends in lab values were seen. Two SAEs, neither treatment-related, occurred several weeks after completion of VE202 dosing: abdominal pain caused by a suspected passed bile duct stone (Day 71) and hip pain leading to hip replacement (Day 120). Sustained VE202 strain detection (Figure 1) and relative abundance (Figure 2) in the vancomycin-perturbed gut was seen as soon as Day 2, sustained through 2 weeks after dosing completion, then declined slowly but remained substantially above baseline through Week 24. A dose- and duration-dependent trend in colonization was seen. CONCLUSION: VE202 is well tolerated in healthy adults and provides robust, durable, abundant colonization of LBP strains.