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SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered concurrently with intravenous β-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess β-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).

SYN-004 was well tolerated up to a single oral dose of 750 mg and multiple doses of 300 mg every 6 h for 7 days. The pharmacokinetic results support that SYN-004 remained localized in the intestine.

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Background Clostridium difficile infections (CDI) are an “urgent threat,” but there are no approved drugs or vaccines to prevent new onset CDI. SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered with IV β-lactam antibiotics and remain localized in the intestine to degrade antibiotics excreted into the intestine. This is expected to protect the gut microbiome from disruption thus preventing deleterious effects including CDI, colonization by opportunistic pathogens, and emergence of antibiotic resistance in the gut microbiome. Ribaxamase was well tolerated and not systemically absorbed in Phase 1 studies and efficiently degraded ceftriaxone excreted into the human intestine while not altering the plasma pharmacokinetics of ceftriaxone in Phase 2a studies.MethodsA multinational Phase 2b, double-blind, placebo-controlled, study was conducted to determine whether ribaxamase could prevent new onset CDI with additional endpoints for non-CDI antibiotic-associated diarrhea, colonization by opportunistic pathogens, changes in the gut microbiome and emergence of antibiotic resistance. The 412 patient mITT population, enriched for higher risk for CDI, were admitted to the hospital for ≥5 days of IV ceftriaxone for the treatment of a lower respiratory tract infection. Patients were randomized 1:1 to receive ribaxamase or placebo during treatment and for 72h after. Fecal samples were collected at prespecified points for determination of colonization by opportunistic pathogens and to examine changes in the gut microbiome. Patients were monitored for 6 weeks for CDI (diarrhea plus the presence of C. difficile toxin). The study was powered at 80% for the reduction in CDI with 1-sided α = 0.05.ResultsThe study met its primary endpoint with a 71% relative risk reduction in CDI (1-sided p = 0.045) and had a statistically significant 44% relative risk reduction in new colonization by vancomycin-resistant enterococci (1-sided p = 0.0002). Ribaxamase also protected the diversity of the gut microbiome and reduced the emergence of antibiotic resistance in ceftriaxone-treated patients.ConclusionThese data support that ribaxamase can maintain the balance of the gut microbiome and thereby prevent opportunistic infections like CDI during IV β-lactam treatment.Disclosures J. Kokai-Kun, Synthetic Biologics, Inc.: Employee, Salary; T. Roberts, Synthetic Biologics, Inc.: Employee, Salary; O. Coughlin, Synthetic Biologics, Inc.: Employee, Salary; H. Whalen, Synthetic Biologics, Inc.: Employee, Salary; C. Le, Synthetic Biologics, Inc.: Employee, Salary; C. Da Costa, Synthetic Biologics, Inc.: Employee, Salary; J. Sliman, Synthetic Biologics, Inc.: Employee, Salary.