ePHex: a phase 3, double-blind, placebo-controlled, randomized study to evaluate long-term efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria

Abstract

Background: Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH.

Methods: Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m²) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint.

Results: Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52, O. formigenes was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was - 3.80 μmol/L; 95% CI: - 7.83, 0.23; p-value = 0.064). Kidney function remained stable in both treatments.

Conclusions: Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (p = 0.06). A subtle effect observed with Oxabact suggests that O. formigenes may aid in preventing kidney stones. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Oxabact; Oxalate; Oxalobacter formigenes; Primary hyperoxaluria; eGFR.

Fig. 1

CONSORT diagram showing subject disposition. *There were two initial screen failures (one subject had an initial eGFR too high and one subject had an initial Pox that was too low); the subjects were rescreened and different subject numbers were obtained. eGFR = estimated glomerular filtration rate; FAS = full analysis set; IMP = investigational medicinal product; PPS = per protocol set; SAF = safety population

Fig. 2

a Mean total plasma oxalate over time — full analysis set. b. Mean free plasma oxalate over time — full analysis set. Error bars depict standard error

Fig. 3

Mean estimated glomerular filtration rate over time — full analysis set, absolute values. Error bars depict standard error. Estimated glomerular filtration rate was calculated using the creatinine-based Bedside Schwartz formula in children (< 18 years) or the Chronic Kidney Disease Epidemiology Collaboration formula for adults (≥ 18 years).

Fig. 4

Mean change from baseline of non-centrifuged urinary oxalate excretion over time — full analysis set. Error bars depict standard error