Introduction: Kidney stone risk and association with urine oxalate (UOx) levels in enteric hyperoxaluria (EH)
Methods: URIROX-1, a Phase 3 double-blind RCT, evaluated efficacy and safety of reloxaliase (7,500 units or placebo [PBO] 3-5x/day orally for 4 weeks) in EH patients with 24h UOx = 50 mg/24h despite standard of care. The primary efficacy endpoint was percent change from baseline in 24h UOx. Secondary efficacy endpoints included proportion of subjects with = 20% reduction in 24h UOx and analysis of efficacy parameters in the bariatric surgery (BS) subgroup.
Results: Reloxaliase produced a 22.6% reduction in 24h UOx vs 9.7% with PBO [difference -14.3% (p=0.0040)], with more profound effect in the BS subgroup [-16.2% (p=0.013)]. More subjects on reloxaliase (48.3%) vs PBO (31.6%) achieved a = 20% reduction in 24h UOx, with greater effect in BS (50% on reloxaliase vs 28.9% on PBO). GI adverse events were more common with reloxaliase, but most were mild or moderate in severity and no reloxaliase subject discontinued treatment as a result. Of 115 randomized subjects, 15 reported KS passage during the 8 week study, revealing a higher KS event rate (0.78/year) than anticipated by limited EH epidemiologic data available. Baseline 24h UOx levels of these 15 subjects was markedly higher (mean [median] 107.2 [98.5] mg/d vs 86.5 [77.5] mg/d).
Conclusions: URIROX-1 is the first RCT examining a specific therapy targeting UOx reduction in EH, a clinically challenging and understudied population. The URIROX-1 study demonstrated a clinically meaningful reduction of 24h UOx in EH subjects on reloxaliase. Although the short duration of this study precludes assessment of its effect on KS risk, the URIROX-1 data underscores the utility of 24h UOx as a surrogate marker of KS risk and the value of the ongoing URIROX-2 adaptive design trial to quantify clinical benefits of reloxaliase with respect to KS disease progression and renal function. Source of