Abstract
Background
SYN-004 is an orally administered β-lactamase enzyme, designed to be given concurrently with certain intravenous β-lactam antibiotics like cephalosporins. SYN-004 is intended to degrade residual antibiotics excreted into the intestine as a result of hepatobiliary excretion and to prevent the disruption of the gut microbiome by these excess antibiotics. Preserving the gut microbiome is expected to prevent secondary infections by pathogens like Clostridium difficile and protect against other antibiotic-associated diarrheas.
Methods
Two, randomized, double blind, placebo-controlled Phase 1 clinical studies were conducted in normal healthy adult volunteers to assess the tolerability and systemic absorption of single and multiple doses of SYN-004. A single-ascending dose study investigated single oral doses of 75–750 mg SYN-004 and was conducted in 40 subjects (five cohorts of six active and two placebo subjects). A multiple-ascending dose study investigated doses of 75–300 mg SYN-004, administered every 6 h for 7 days and was conducted in 24 subjects (three cohorts of six active and two placebo subjects). The safety and tolerability of SYN-004 was assessed and serial plasma and serum samples were collected to assess the pharmacokinetics and potential immunogenicity of SYN-004.
Results
Minimal and mild adverse events were reported in ~30 % of the subjects who received active drug and placebo and no antidrug antibodies were detected in any subject. Analysis of serial plasma samples demonstrated negligible systemic bioavailability of SYN-004 with most plasma concentrations being below the lower limit of quantitation (0.8 ng/mL) for the assay. SYN-004 was well tolerated in the 48 subjects who received active drug, and adverse events in those subjects were comparable to the 16 subjects who received placebo, up to the maximum doses administered in each study.
Conclusion
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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Acknowledgments
The authors would like to thank Dr. Carol Reed for helpful advice on trial design, Susan Curry and the team at Ce3, Inc. (Guilford, CT, USA) for conducting the study and Sevan Broughlan and the technical team at WIL Research (Skokie, IL, USA) for development, validation and performance of the SYN-004 detection and anti-drug antibody assays.
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Funding
These studies were sponsored and fully funded by Synthetic Biologics, Inc.
Conflict of interest
TR, JFK-K, OC, HW, JAB, SH and JS are employees of Synthetic Biologics. JL is a paid consultant to Synthetic Biologics. BVL and KL’s institution received fees to conduct the described clinical studies.
Ethical approval
Both studies were conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki (1964) and consistent with the International Conference of Harmonization (ICH)/Good Clinical Practice and applicable regulatory requirements.
Informed consent
Subjects who agreed to participate in the studies signed an Institutional Review Board-approved informed consent before any study procedures were done and were provided a copy of the signed document.
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Roberts, T., Kokai-Kun, J.F., Coughlin, O. et al. Tolerability and Pharmacokinetics of SYN-004, an Orally Administered β-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies. Clin Drug Investig 36, 725–734 (2016). https://doi.org/10.1007/s40261-016-0420-0
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DOI: https://doi.org/10.1007/s40261-016-0420-0