Theriva Biologics, Inc. (NYSE American: TOVX) announced that the Data and Safety Monitoring Committee (DSMC) has recommended the continuation of its Phase 1b/2a clinical trial of SYN-004 (ribaxamase) into Cohort 3. This decision follows a review of the safety and pharmacokinetic data from Cohort 2, which focused on allogeneic hematopoietic cell transplant (HCT) recipients for the prevention of acute graft-versus-host-disease (aGVHD).
The Phase 1b/2a trial is a randomized, double-blinded, placebo-controlled study conducted at Washington University School of Medicine in St. Louis. It aims to assess the safety, tolerability, and potential absorption of oral SYN-004 (150 mg QID for up to 28 days) in allogeneic HCT recipients receiving intravenous (IV) antibiotics. The trial design includes three sequential cohorts, each evaluating a different study-assigned IV beta-lactam antibiotic. Cohort 1 used meropenem, while Cohort 2 used piperacillin/tazobactam, and Cohort 3 will use cefepime.
Safety and Pharmacokinetic Findings
Cohort 2 enrolled 19 patients, with 18 receiving at least one dose of IV piperacillin/tazobactam, and 12 completing sufficient doses to be evaluable for the study endpoints. The blinded data from Cohort 2 revealed that adverse events (AEs) and serious adverse events (SAEs) were consistent with those typically observed in allo-HCT patients. Importantly, investigators determined that no AEs or SAEs were related to the SYN-004 treatment. Among the reported SAEs, infections and infestations, including sepsis, were the most common.
Notably, no patients died within the 30-day follow-up period after the last dose of the study drug. One patient died 95 days post-treatment due to cancer relapse, and another died 211 days post-treatment due to pneumonia; neither death was related to SYN-004.
Consistent with Cohort 1 and previous studies, no patient blood samples tested positive for SYN-004 at any timepoint, indicating minimal systemic absorption. The pharmacokinetics of piperacillin, which can be metabolized by SYN-004, were as expected for this patient population.
Implications for aGVHD Prevention
SYN-004 (ribaxamase) is designed as an oral prophylactic therapy to degrade certain IV beta-lactam antibiotics within the GI tract. This action helps maintain the natural balance of the gut microbiome, preventing Clostridioides difficile infection (CDI), overgrowth of pathogenic organisms, the emergence of antimicrobial resistance (AMR), and aGVHD in allogeneic HCT recipients. Allogeneic HCT recipients often require long courses of IV beta-lactam antibiotics, which can disrupt the gut microbiome and lead to adverse outcomes.
Steven A. Shallcross, Chief Executive Officer of Theriva Biologics, stated, "These encouraging data support the clinical advancement of SYN-004 and build on the growing data that underscore its therapeutic potential... We are very grateful for the tremendous support from Dr. Dubberke and his team at Washington University as we pursue additional funding to enable the conduct of the third cohort and continue with the goal of improving standard treatment for these highly susceptible patients by overcoming existing limitations of broad-spectrum IV beta-lactam antibiotics."
Trial Design and Further Development
The Phase 1b/2a trial is expected to enroll up to 36 participants. The primary endpoint is safety and tolerability, with secondary endpoints including the impact of SYN-004 on the gut microbiome and preliminary therapeutic benefits. A previous Phase 2b clinical trial involving 412 patients demonstrated that SYN-004 protected the gut microbiome from antibiotic-mediated dysbiosis and reduced the incidence of new colonization by opportunistic microorganisms.
