Phase 1b/2a Evaluation of the Safety and Tolerability of SYN-004 in Adult Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Recipients

Arguably one of the greatest medical breakthroughs in the 20th century was the introduction of antibiotics into clinical use. Soon afterwards several downsides to antibiotics were recognized, including antibiotic-associated colitis (now known to be due to Clostridioides difficile) and emergence of antibiotic-resistant organisms (ARO) that colonize the gut. CDI and ARO are now urgent threats to human health. The healthy human gut microbiome provides colonization resistance against C. difficile and ARO, and antibiotic-induced gut microbiome disruption leads to C. difficile and ARO colonization, infection, and transmission to other people. Unfortunately, patient populations that have benefited the most from antibiotics, such as HCT recipients, are now at greatest risk for CDI and ARO infections. SYN-004 (ribaxamase) is an orally administered recombinant class A beta-lactamase that breaks down beta-lactam antibiotics in the gut and has been found to protect against gut microbiome disruption, C. difficile and ARO colonization, and C. difficile infection (CDI) during IV beta-lactam exposures in people. Due to the high incidence of CDI and ARO infections, HCT recipients are a potential target population for phase 3 trials of SYN-004 to prevent these infections. However, HCT recipients often have significant disruption of the gut mucosal barrier, which may lead to absorption of biologically active SYN-004 and reduction in systemic antibiotic efficacy. Therefore, with this application we propose to complete a phase 1b/2a clinical trial investigating the potential for systemic absorption of biologically active SYN-004 and impact SYN-004 has on cefepime (FEP) pharmacokinetics (PK), the microbiome, and C. difficile and ARO colonization in HCT recipients with the following aims: Aim 1: Determine if there is systemic absorption of biologically active SYN-004 and/or alterations in FEP PK among allogeneic HCT recipients who receive myeloablative conditioning compared to placebo; Aim 2: Define the gut microbiome composition and metabolic function sparing effects of SYN-004 compared to placebo in allogenic HCT recipients who receive FEP; and Aim 3: Characterize the acquisition and abundance of AROs and AR genes in the guts of allogenic HCT recipients who receive SYN-004 versus placebo during cefepime administration. We hypothesize systemic absorption of biologically active SYN-004 will not be detected in HCT recipients and FEP PK will not be altered, and that SYN-004 recipients will have less microbiome disruption and C. difficile and ARO colonization/abundance compared to placebo. The rationale and motivation for this study are novel approaches to prevent CDI and ARO are urgently needed. Our proposal is significant because CDI and ARO are urgent problems. Our proposal is innovative because SYN-004 protection of the gut microbiome will change current paradigms to treat infections and prevent CDI and AROs. The proposed work is impactful because this phase 1b/2a trial will provide supporting evidence and justification for a phase 3 trial with a primary outcome of CDI prevention in HCT recipients. Project Number: 1U01AI195139-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: ERIK DUBBERKE (+1 co-PI) | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $919,820 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-U (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1U01AI19513901