You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy (PD21)1 Sep 2021PD21-10 SAFETY AND TOLERABILITY OF AN OXALATE-CONSUMING SYNTHETIC BIOTIC MEDICINE: SYNB8802 IN HEALTHY VOLUNTEERS WITH INDUCED DIETARY HYPEROXALURIA Marja Puurunen, William Denney, Shawn Searle, Sushama Scalera, Andrew Marsh, David Lubkowicz, Caroline Kurtz, Aoife Brennan, and Richard Riese Marja PuurunenMarja Puurunen More articles by this author , William DenneyWilliam Denney More articles by this author , Shawn SearleShawn Searle More articles by this author , Sushama ScaleraSushama Scalera More articles by this author , Andrew MarshAndrew Marsh More articles by this author , David LubkowiczDavid Lubkowicz More articles by this author , Caroline KurtzCaroline Kurtz More articles by this author , Aoife BrennanAoife Brennan More articles by this author , and Richard RieseRichard Riese More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002010.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: High urinary oxalate levels (UOx) in patients with enteric hyperoxaluria (EH) can lead to recurrent kidney stones, nephrocalcinosis and chronic kidney disease (CKD). There are currently no approved pharmacological therapies for treating hyperoxaluria. SYNB8802 was developed by engineering a pathway for oxalate degradation in a probiotic strain of Escherichia coli Nissle 1917. SYNB8802 is an orally administered, non-systemically absorbed, non-colonizing live biotherapeutic developed for the treatment of EH. SYNB8802 acts in the gastrointestinal (GI) tract to convert oxalate to formate and CO2, two naturally occurring GI metabolites, to reduce urinary oxalate in patients with EH. METHODS: Adult healthy volunteers (HV) were enrolled in a multiple ascending dose study. Subjects started a high oxalate, low calcium diet run-in 4 days prior to first dose of the investigational product. They were then randomized (6 active:3 placebo) to receive 5 days of SYNB8802 or placebo TID, with the option of a 2-day dose-ramp period. 24hr UOx levels were measured daily. The primary outcome was safety and tolerability of SYNB8802. Secondary outcome was microbial kinetics of SYNB8802 in feces by qPCR. Exploratory outcomes assessed the effect of SYNB8802 on 24hr UOx excretion, UOx:U-creatinine ratio, and U-supersaturation biomarkers. RESULTS: Total of 45 HV were enrolled in 5 dose cohorts of 9 subjects each. There were no treatment-related serious adverse events or systemic toxicity. Adverse events were mainly classified as mild or moderate and mostly GI-related. Nausea and vomiting were dose-limiting at higher doses. Implementation of a 2-day dose-ramp limited adverse events. The maximum tolerated dose was 3x1011 live cells. There were no signs of colonization and all subjects cleared the bacteria after the last dose. Baseline UOx levels were increased to induce temporary dietary hyperoxaluria. A >20% decrease in 24hr UOx excretion was observed in SYNB8802 treated subjects compared with placebo at a well-tolerated dose. CONCLUSIONS: These results provide proof of mechanism for UOx lowering by the Synthetic Biotic medicine SYNB8802 through consumption of oxalate within the GI tract. SYNB8802 was well-tolerated at a potentially clinically meaningful dose. Further clinical development as a potential novel treatment for EH is warranted. Source of Funding: Synlogic Inc © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e378-e378 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marja Puurunen More articles by this author William Denney More articles by this author Shawn Searle More articles by this author Sushama Scalera More articles by this author Andrew Marsh More articles by this author David Lubkowicz More articles by this author Caroline Kurtz More articles by this author Aoife Brennan More articles by this author Richard Riese More articles by this author Expand All Advertisement Loading ...