Abstract: PO2026
Proof-of-Concept Study of Oxalate-Consuming Synthetic Biotic Medicine SYNB8802 in Enteric Hyperoxaluria after Roux-en-Y Surgery
Session Information
- Clinical Pharmacology, Pharmacokinetics, and Drug Toxicity in Kidney Diseases
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Puurunen, Marja, Synlogic, Cambridge, Massachusetts, United States
- Denney, William, Human Predictions LLC, Cambridge, Massachusetts, United States
- Ndugga-Kabuye, Mesaki Kenneth, Synlogic, Cambridge, Massachusetts, United States
- Marsh, Andrew, Synlogic, Cambridge, Massachusetts, United States
- Lubkowicz, David, Synlogic, Cambridge, Massachusetts, United States
- Kurtz, Caroline B., Synlogic, Cambridge, Massachusetts, United States
- Brennan, Aoife M., Synlogic, Cambridge, Massachusetts, United States
- Riese, Richard, Synlogic, Cambridge, Massachusetts, United States
Background
High urinary oxalate levels (UOx) in patients with enteric hyperoxaluria (EH) can lead to recurrent kidney stones, nephrocalcinosis and chronic kidney disease. SYNB8802 is an engineered E. coli Nissle 1917 that contains an oxalate degradation pathway which converts oxalate to formate within the gastrointestinal (GI) tract, thereby reducing urinary oxalate. SYNB8802 is an oral, non-colonizing live biotherapeutic developed for the treatment of EH. SYNB8802 is explored in a Phase 1a/b study in healthy volunteers (HV) and Roux-en-Y (RYGB) patients with hyperoxaluria.
Methods
In Part A of the study [NCT04629170] hyperoxaluria was induced in adult HV by a high oxalate (400-600mg), low calcium (400mg) diet over 4 days. Subjects were then randomized (6 active:3 placebo) to receive 5 days of SYNB8802 or placebo TID. 24hr UOx levels were measured daily. Primary outcome was safety and tolerability. Part B is a double-blind, placebo-controlled crossover study of SYNB8802 in subjects with enteric hyperoxaluria and a history of RYGB. Up to 20 subjects will be randomized in a crossover design with a 2-week washout period to receive SYNB8802 (at 3e11 live cells/dose) or placebo, dosed up to TID with meals. Urine samples for determination of 24hr UOx levels will be collected over 3 days at baseline and on the last 3 days of each dosing period. Subjects will maintain their normal diet throughout the study. The primary endpoint is change from baseline in 24hr UOx amount excreted with SYNB8802 treatment versus placebo. Secondary endpoints include change from baseline in UOx:creatinine ratio with SYNB8802 treatment versus placebo.
Results
In Part A, a well-tolerated dose of 3e11 live cells was identified in HV. At this dose, the percent change from baseline UOx levels was -28.6% (90% CI: -42.4 to -11.6) compared to placebo in diet-induced hyperoxaluria. This dose is being studied in Roux-en-Y patients with hyperoxaluria in Part B. The results from the RYGB population will be reported.
Conclusion
These results provide proof of mechanism for UOx lowering by SYNB8802 through GI consumption of oxalate in diet-induced hyperoxaluria. Part B seeks proof-of-concept in patients with enteric hyperoxaluria.
Funding
- Commercial Support –