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Abstract: TH-OR19

Pharmacodynamic (PD) Profiling of Reloxaliase in Patients with Severe Hyperoxaluria

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Knauf, Felix, 1University Hospital Charite, Berlin, Germany
  • Grujic, Danica, Allena Pharmaceuticals, Newton, Massachusetts, United States
  • Keddis, Mira T., 3Mayo Clinic Hospital, Phoenix, Arizona, United States
  • Weeks, Alicia, Allena Pharmaceuticals, Newton, Massachusetts, United States
  • Kausz, Annamaria T., Allena Pharmaceuticals, Newton, Massachusetts, United States
Background

Hyperoxaluria is a major risk factor for kidney stones and can lead to chronic kidney disease (CKD). With decreasing kidney function, plasma oxalate (POx) rises and oxalate may deposit in the kidneys and other tissues (systemic oxalosis) leading to ESRD. Reloxaliase (REL), a non-absorbed, oxalate specific oral enzyme therapy designed to degrade oxalate along the GI tract, may potentially reduce the systemic and renal oxalate burden in patients with enteric and primary hyperoxaluria (EH and PH). This study tested the PD of REL, and addressed questions regarding potential formate accumulation (by-product of oxalate degradation) and systemic absorption of oxalate decarboxilase (OxDc, the active component of REL).

Methods

This 12-week, open label study enrolled subjects with EH, CKD and hyperoxalemia (UOx ≥40mg/d, eGFR <45mL/min and POx>5μmol/L, n=10) and PH (UOx ≥40 mg/d, n=5) who received 7,500u of REL 5x/day with meals/snacks. Parameters assessed at baseline, and weeks 4, 8 and 12 included POx and UOx (only if eGFR >15mL/min), plasma formic acid (pre- and post-prandial/post-dose; Q2 Solutions) and OxDc (specific ELISA, Absorption Systems).

Results

Reported adverse events (AEs) were mostly GI related; there were no related serious AEs. In EH, both POx and UOx decreased substantially; in PH, UOx did not change, and POx stayed normal at baseline and during treatment (Table). There was no formate accumulation, as all samples were below or within normal range (1-9mg/L). Similarly, there was no detectable absorption of REL, as all samples were below the limit of detection of the assay for OxDc (<0.0001% of the administered dose of 37,500 u/day).

Conclusion

Reloxaliase was well tolerated; the absence of formate accumulation further supports its safety. The lack of REL absorption, in addition to supporting low potential for systemic toxicity, confirms its site of action within the GI tract. This best aligns with the pathophysiology of EH as evidenced by the substantial reduction in both POx and UOx in EH subjects with CKD/ESRD.

Funding

  • Commercial Support