A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria

Abstract

Primary hyperoxaluria (PH) patients overproduce oxalate because of rare genetic errors in glyoxylate metabolism. Recurrent urolithiasis and/or progressive nephrocalcinosis are PH hallmarks and can lead to kidney damage, systemic oxalosis and death. Based on previous studies, we hypothesised that treatment with the oxalate-metabolizing bacterium Oxalobacter formigenes would mediate active elimination of oxalate from the plasma to the intestine of PH patients, thereby reducing urinary oxalate excretion (Uox). The efficacy and safety of O. formigenes (Oxabact™ OC3) were evaluated for 24 weeks in a randomised, placebo-controlled, double-blind study. The primary endpoint was reduction in Uox. Secondary endpoints included change in plasma oxalate (Pox) concentration, frequency of stone events, number of responders, and Uox in several subgroups. Additional post hoc analyses were conducted. Thirty-six patients were randomised; two patients withdrew from placebo treatment. Both OC3 and placebo groups demonstrated a decrease in Uox/urinary creatinine ratio, but the difference was not statistically significant. No differences were observed with respect to change in Pox concentration, stone events, responders’ number or safety measures. In patients with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2, Pox increased by 3.25 µmol/L in the placebo group and decreased by −1.7 µmol/L in the OC3 group (p = 0.13). After 24 weeks, eGFR had declined to a greater degree in the placebo than in the OC3 group: −8.00 ± 2.16 versus −2.71 ± 2.50; p = 0.01. OC3 treatment did not reduce urinary oxalate over 24 weeks of treatment compared with placebo in patients with PH. The treatment was well tolerated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00240-017-0998-6) contains supplementary material, which is available to authorized users.

Functional eubacteria species along with trans-domain gut inhabitants favour dysgenic diversity in oxalate stone disease

“…Despite maintaining of an ecosystem the colonization of Oxalobacter formigenes inside the human gut as healthy gut flora 10 describing the withholds host health features and other core microbiome as well 9 . As their absence corresponds to enhanced level of oxalate in systemic fluid 49 , replacement therapy granted the recovery from hyperoxaluria condition in humans 50 . Demonstrating the colonization status of Oxalobacter formigenes , we speculate the major role of this bacterium in settlement of functional eubacteria and trans-domain species as well as in symptomatic phase of hyperoxaluria i.e.…”

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition

“…Primary hyperoxaluria describes a group of inborn errors of metabolism where defective liver enzymes involved in glyoxylate metabolism result in excess production of oxalate [49]. The predominant route of oxalate excretion is via the kidneys, with enteric excretion also playing a role when renal function is impaired [50]. In primary hyperoxaluria, excessive oxalate levels supersaturate renal excretion mechanisms, leading initially to calcium oxalate deposition within the kidney, and subsequently systemic oxalosis (deposition of oxalate within other systems) affecting the skeleton, heart, liver and other organs [49].…”

“…The evolution of our treatment of this condition therefore hinges upon identifying therapeutic targets which do not necessitate organ transplantation to replace the defective enzyme. Trials utilising the oxalate-metabolising bacterium Oxabacter formigenes to increase gut excretion of oxalate and reduce urinary oxalate excretion reached phase II/III trials but did not significantly reduce urinary oxalate excretion [50]. Animal studies have shown oxalate decarboxylase enzymes can effectively reduce urinary oxalate levels, providing an alternative potential future therapy for reduction of calcium-oxalate nephrocalcinosis in primary hyperoxaluria [53,54].…”

Plant Extracts in Hyperoxaluria Treatment: A Review of Experimental and Clinical Research

“…[9,12,13] A probiotic approach with the use of O. formigenes, Eubacterium lentum, Lactobacillus acidophilus and all other microorganisms is considered promising today. [14,15] A substantial body of research has been conducted on the ability of probiotics to reduce oxalate excretion. These studies have led to promising, but, all in all, ambiguous results requiring confirmation with the help of larger, welldesigned randomized clinical trials.…”