Ribaxamase Shows Safety in the Prevention of aGVHD Following Allo-HSCT

Steven A. Shallcross

Safety and pharmacokinetic data from the second cohort of a phase 1b/2a study (NCT04692181) of ribaxamase (SYN-004) for the prevention of acute graft-vs-host-disease (aGVHD) in patients who received allogeneic hematopoietic stem cell transplant (allo-HSCT) support the initiation of enrollment for a third cohort, based on a recommendation from the trial’s Data and Safety Monitoring Committee (DSMC).¹

In cohort 3, patients will receive ribaxamase or placebo in combination with intravenous (IV) beta-lactam antibiotic cefepime.

Patients in cohort 2 (n = 19) were randomly assigned 2:1 to receive ribaxamase or placebo. Most patients (n = 18) received at least 1 dose of IV piperacillin/tazobactam, and 12 of these patients completed sufficient doses of IV piperacillin/tazobactam to make them evaluable for the study’s end points. The study is ongoing and remains blinded.

Preliminary safety findings showed that adverse effects (AEs) and serious AEs (SAEs) were consistent with those usually reported in patients who receive allo-HSCT; no AEs or SAEs were deemed to be related to study treatment by investigators. Fifteen SAEs were observed in 10 patients, the most common of which were infections and infestations, including sepsis. During the 30-day follow-up period, no patients died after the last dose of study drug; however 1 patient died 95 days after the last dose due to cancer relapse, and another died 211 following the final dose due to pneumonia. Neither of these deaths were deemed related to the study drug.

“These encouraging data support the clinical advancement of [ribaxamase] and build on the growing data that underscore its therapeutic potential,” Steven A. Shallcross, chief executive officer of Theriva Biologics, stated in a news release. “The first 2 cohorts have shown that active [ribaxamase] is not found in the blood of patients [undergoing allo-HSCT] after repeated oral doses, in part alleviating the concern that [ribaxamase] might be absorbed in patients with poor intestinal barrier function and potentially interfere with IV antibiotics. We are very grateful for the tremendous support from [Erik R. Dubberke, MD, MSPH] 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.”

Ribaxamase is an oral prophylactic agent that degrades certain IV beta-lactam antibiotics within the gastrointestinal tract. Through this mechanism, the therapy maintains the natural balance of the gut microbiome for the prevention of Clostridioides difficile infection, overgrowth of pathogenic organisms, the emergence of antimicrobial resistance, and aGVHD in allo-HSCT recipients.

The single-center, placebo-controlled, double-blinded phase 1b/2a trial is enrolling adult patients who were undergoing myeloablative allo-HSCT for a hematologic malignancy or myeloproliferative disorder. The study is designed to examine the safety, tolerability, and potential absorption of oral ribaxamase into the systemic circulation of allo-HSCT recipients who were also treated with an antibiotic.^1,2

Patients received oral ribaxamase at 150 mg 4 times daily for up to 28 days. Those in cohort 1 received meropenem as the study-assigned antibiotic; patients in cohort 2 were treated with piperacillin/tazobactam, and those in cohort 3 will receive cefepime. The study will enroll up to 36 total patients.¹

The primary end points are systemic absorption of ribaxamase, systemic antibiotic concentrations, bacteremia, bacterial intestinal infections, grade 3 or 4 AEs, and overall survival. Secondary outcomes included frontline failure of piperacillin/tazobactam or cefepime, gut microbiome protection, urine concentrations of 3-indoxyl sulfate, and impact on immunosuppressant dosing.²

References

1. Theriva Biologics announces positive outcome of Data and Safety Monitoring Committee (DSMC) review in phase 1b/2a clinical trial of SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant recipients. News release. Theriva™ Biologics, Inc. October 3, 2024. Accessed October 3, 2024. https://therivabio.com/press_releases/theriva-biologics-announces-positive-outcome-of-data-and-safety-monitoring-committee-dsmc-review-in-phase-1b-2a-clinical-trial-of-syn-004-ribaxamase-in-allogeneic-hematopoietic-cell-trans/
2. SYN-004 safety and tolerability in allo-HCT subjects. ClinicalTrials.gov. Updated October 13, 2023. Accessed October 3, 2024. https://www.clinicaltrials.gov/study/NCT04692181