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

Höppe, Bernd; Niaudet, Patrick; Salomon, Rémi; Harambat, Jérôme; Hulton, Sally‐Anne; Hoff, William van’t; Moochhala, Shabbir H.; Deschênes, Georges; Lindner, Elisabeth; Sjögren, Anna; Cochat, Pierre

doi:10.1007/s00467-016-3553-8

Cited by 67 publications

(48 citation statements)

References 32 publications

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“…This study revealed some unexpected effects of OC5 including an increased urinary excretion of oxalate and calcium; this suggested that systemic calcium oxalate deposits might be mobilised [32]. These findings, taken together with the important factors for progression to ESRD in PH patients as described by Zhao et al [16], resulted in the decision to conduct post hoc analyses to investigate the same effects in the OC3-DB-02 study.…”

Section: Discussionmentioning

confidence: 88%

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

2017

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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.

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Section: Discussionmentioning

confidence: 88%

“…After completion of this study, improvements in manufacturing methods and validation assays resulted in a new, more concentrated formulation, OC5 [32]. OC5 is currently undergoing further clinical trial evaluation.…”

Section: Discussionmentioning

confidence: 99%

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

2017

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“…Oxalate itself has been the target of potential therapies with oxalate degrading enzymes or bacteriacontaining probiotics. Although the clinical benefits of Oxalobacter formigenes administration have not been clearly demonstrated, efforts are ongoing to degrade some of the oxalate produced by the liver as a therapeutic strategy (Hoppe et al 2016). By preventing crystal growth with novel approaches (Chung et al 2016), protecting the kidneys from AKI and controlling the inflammatory response to calcium oxalate deposits, in addition to the current conservative measures, we could preserve renal function in ways that aggressive therapies, such as liver and kidney transplantation, might not be needed in most PH1 patients.…”

Section: Combined Molecular Therapymentioning

confidence: 99%

Molecular therapy of primary hyperoxaluria

Martín-Higueras

Torres

Salido

2017

J of Inher Metab Disea

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During the last few decades, the molecular understanding of the mechanisms involved in primary hyperoxalurias (PHs) has set the stage for novel therapeutic approaches. The availability of PH mouse models has facilitated preclinical studies testing innovative treatments. PHs are autosomal recessive diseases where the enzymatic deficit plays a central pathogenic role. Thus, molecular therapies aimed at restoring such deficit or limiting the consequences of the metabolic derangement could be envisioned, keeping in mind the specific challenges posed by the cell-autonomous nature of the deficiency. Various molecular approaches like enzyme replacement, substrate reduction, pharmacologic chaperones, and gene and cell therapies have been explored in cells and mouse models of disease. Some of these proof-of-concept studies have paved the way to current clinical trials on PH type 1, raising hopes that much needed treatments will become available for this severe inborn error of metabolism.

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“…Multiple gut microbes can degrade oxalate [22], including Oxalobacter formigenes, an oxalate autotroph [23][24][25][26][27]. When given to animals, O. formigenes has reduced host oxalate burden [28][29][30][31][32][33]. [44][45][46].…”

Section: Mainmentioning

confidence: 99%

Microbial contributions to oxalate metabolism in health and disease

Liu

Devlin

et al. 2020

Preprint

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Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbiota can degrade oxalate and protect against its absorption. However, the particular microbes that actively degrade oxalate in vivo are ill-defined, which restricts our ability to disentangle the underlying taxonomic contributions. Here we leverage large-scale multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota in health harbors diverse ODP-encoding microbial species, but an oxalate autotroph-Oxalobacter formigenes- dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) are at significantly increased risk for disrupted oxalate homeostasis and calcium-oxalate nephrolithiasis. Here, by analyzing multi-omics data from the iHMP-IBD study, we demonstrate that the oxalate degradation function conferred by the intestinal microbiota is severely impaired in IBD patients. In parallel, the enteric oxalate levels of IBD patients are significantly elevated and associated with intestinal disease severity, which is consistent with the clinically known nephrolithiasis risk. The specific changes in ODP expression by several important taxa suggest that they play different roles in the IBD-induced nephrolithiasis risk.

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

Abstract: Treatment with OC5 did not significantly reduce Uox or Pox over 8 weeks of treatment. The treatment was well tolerated and successfully delivered to the gastrointestinal tract.

Cited by 67 publications

References 32 publications

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

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

Molecular therapy of primary hyperoxaluria

Microbial contributions to oxalate metabolism in health and disease

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