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SYN-004 (Ribaxamase), an Oral β-Lactamase, Prevented Clostridium Difficile Infection and Protected Patients from Colonization by Antimicrobial Resistant Pathogens by Preserving Gut Microbiome Diversity in a Phase 2B Clinical Trial
John F. Kokai-Kun, Tracey Roberts, Olivia Coughlin, Heidi Whalen, Chenxiong C. Le, Klaus T. Gottlieb, Joseph Sliman
Synthetic Biologics, Inc., Rockville, MD, United States

SYN-004 (ribaxamase) is an orally administered β-lactamase (an enzyme of 29 kDa) which is designed to be given concurrently with certain IV β-lactam antibiotics. Ribaxamase remains localized in the intestine where it is available to degrade excreted β-lactam antibiotics. This activity should thus protect the gut microbiome from disruption and thereby prevent deleterious side effects including, Clostridium difficile infection (CDI), colonization by opportunistic pathogens and emergence of antibiotic resistance in the gut microbiota. Ribaxamase was well tolerated in Phase 1 studies and efficiently degraded ceftriaxone excreted into the human intestine in Phase 2a studies, where it also did not alter the plasma pharmacokinetics of the ceftriaxone. A global Phase 2b, double-blind, placebo-controlled, study was conducted to determine whether ribaxamase could prevent C. difficile infection with additional endpoints for antibiotic-associated diarrhea, colonization by opportunistic pathogens, changes in the gut microbiome and emergence of antimicrobial resistant organisms in the gut. The modified intent to treat population of the study included 412 patients who were enriched for a higher risk of CDI. These patients were admitted to the hospital for at least 5 days of IV ceftriaxone for treatment of a lower respiratory tract infection. The patients were randomized 1:1 to receive ribaxamase or placebo during and for 72 h after antibiotic treatment. Fecal samples were collected at pre-specified points during the study for determination of colonization by opportunistic pathogens and to examine changes to the fecal microbiome. Patients were also monitored for an additional 6 weeks for CDI (as defined as diarrhea plus the presence of C. difficile toxin as determined by the local clinical laboratory and confirmed at a central laboratory using a toxin ELISA assay). The study was powered at 80% for the reduction in CDI with a 1-sided alpha = 0.05. The study was recently concluded and met its primary endpoint with a 71.4% relative risk reduction in CDI (1-sided p=0.0454) and a statistically significant 43.9% relative risk reduction in new colonization by vancomycin resistant enterococci (1- sided p=0.0002) in the ribaxamase group as compared with the placebo group. Consistent with these findings and the expected mechanism of action of ribaxamase, patients in the ribaxamase group also had significantly less changes and loss of diversity in their gut microbiome as compared with placebo patients following antibiotic treatment. These data are consistent with ribaxamase maintaining the balance of the gut microbiome by degrading β-lactam antibiotics in the intestine and thereby preventing opportunistic infections like C. difficile and colonization by opportunistic pathogens.

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