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)

Saturday, October 5

11:00 AM - 11:15 AM

Room: 144 ABC

Presenting Author(s)

DB

Dmitri Bobilev, MD

VP, Clinical Development
Vedanta Biosciences
Cambridge, MA

Disclosure: Vedanta Biosciences : Employee

Co-Author(s)

SB

Shakti Bhattarai, MS

PhD candidate
University of Massachusetts
N.Dartmouth, Massachusetts

Disclosure: Nothing to disclose
RM

Rajita Menon, PhD

Scientist
Vedanta BIosciences
Cambridge, MA

Disclosure: Vedanta Biosciences: Employee
BK

Brian Klein, PhD

Scientist
Vedanta Biosciences
Cambridge, MA

Disclosure: Vedanta Biosciences: Employee
SR

Shilpa Reddy, MS

Principal Research Associate
Vedanta Biosciences
Cambridge, MA

Disclosure: Vedanta Biosciences: Employee
BO

Bernat Olle, PhD

CEO
Vedanta Biosciences
Cambridge, MA

Disclosure: Vedanta Biosciences: Employee
BR

Bruce Roberts, PhD

CSO
Vedanta Biosciences
Cambridge, MA

Disclosure: Vedanta Biosciences: Employee
VB

Vanni Bucci, PhD

Assistant Professor
University of Massachusetts
N.Dartmouth, Massachusetts

Disclosure: Nothing to disclose
JN

Jason Norman, PhD

Associate Director
Vedanta Biosciences
Cambridge, MA

Disclosure: Vedanta Biosciences: Employee

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 × 10⁹ to 1.1 × 10¹¹ 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 10-100-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 (eg, Proteobacteria) (Fig 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)