1357. The Oral β-Lactamase SYN-004, Designed to Protect the Gut Microbiome from Biliary Excreted IV Antibiotics, Efficiently Degrades Intestinal Ceftriaxone in Two Phase 2a Clinical Trials
Session: Poster Abstract Session: Clinical Trials
Friday, October 28, 2016
Room: Poster Hall
  • IDWeek-2016 Poster.pdf (954.8 kB)
  • Background: SYN-004 is an orally-administered recombinant beta-lactamase designed to be given during treatment with certain IV beta-lactam antibiotics (ABX) for prevention of the adverse effects on the gut microbiome. SYN-004 is designed to be released in the small intestine when the pH > 5.5 to degrade beta-lactam ABX excreted into the intestine via the bile. This is expected to protect the gut microbiome from disruption, prevent secondary infections like C. difficile and reduce emergence of ABX resistance in gut bacteria. SYN-004 must degrade beta-lactam ABX in the GI, without affecting systemic ABX PK. Phase 1 clinical trials of SYN-004 have demonstrated good tolerability with no systemic absorption in healthy volunteers.

    Methods: Two Phase 2a studies have now been conducted in subjects with functioning ileostomies to allow sampling of their intestinal chyme and support the mechanism of action of SYN-004. In the first study, subjects were administered 1 g of IV ceftriaxone (CRO) alone and in combination with one of two dose strengths of SYN-004. In the second study, CRO plus SYN-004 was administered in the presence or absence of the proton pump inhibitor (PPI), esomeprazole, to determine the effect of pH change on SYN-004 activity. Serial plasma and intestinal chyme samples from each study were analyzed for their concentrations of CRO and SYN-004.


    1. SYN-004 effectively degrades CRO excreted into the small intestine

    2. The plasma PK of CRO is unchanged by oral SYN-004 administration

    3. SYN-004 is not detected in the plasma

    4. The use of proton pump inhibitors does not reduce SYN-004 efficacy

    5. SYN-004 is well tolerated when administered with IV CRO

    Of particular importance is that co-administration with a PPI did not impact and may, in some cases, enhance SYN-004’s ability to degrade CRO in the gut. In a hospital clinical setting, this is of importance since many patients are on concomitant PPI therapy.

    Conclusion: These two studies support SYN-004’s ability to degrade certain IV beta-lactam ABX in the human intestine and support progression into a currently enrolling Phase 2b clinical trial to examine its capacity to prevent C. difficile-associated disease and antibiotic-associated diarrhea in patients being treated with IV CRO for lower respiratory tract infection.

    John Kokai-Kun, PhD1, Tracey Roberts, BSN1, Eric Sicard, MD2, Marianne Rufiange, PhD, PMP2, Richard Fedorak, MD3, Christian Carter, PhD3, Olivia Coughlin, PhD1, Heidi Whalen, MHS1, Klaus Gottlieb, MD1 and Joseph Sliman, MD, PhD1, (1)Synthetic Biologics, Inc., Rockville, MD, (2)Algorithme Pharma, Laval, QC, Canada, (3)Northern Alberta Clinical Trials and Research Centre, Edmonton, AB, Canada


    J. Kokai-Kun, Synthetic Biologics, Inc.: Employee , Salary

    T. Roberts, Synthetic Biologics, Inc.: Employee , Salary

    E. Sicard, None

    M. Rufiange, None

    R. Fedorak, None

    C. Carter, None

    O. Coughlin, Synthetic Biologics, Inc.: Employee , Salary

    H. Whalen, Synthetic Biologics, Inc.: Employee , Salary

    K. Gottlieb, Synthetic Biologics, Inc.: Employee , Salary

    J. Sliman, Synthetic Biologics, Inc.: Employee , Salary

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