Abstract: TH-PO1071

ALLN-177, a Novel Oral Enzyme Therapy, Reduces Urinary Oxalate Excretion and Plasma Oxalate in Porcine Dietary Model of Severe Hyperoxaluria

Session Information

Category: Mineral Disease

  • 1204 Mineral Disease: Nephrolithiasis

Authors

  • Grujic, Danica, Allena, Newton, Massachusetts, United States
  • Szczurek, Paulina, Lund University, Lund, Sweden
  • Mosiichuk, Nadia, Lund University, Lund, Sweden
  • Lozinska, Liudmyla, Lund University, Lund, Sweden
  • Pierzynowski, Stefan, Lund University, Lund, Sweden
Background

Hyperoxaluria (HO) is a chronic metabolic disorder and a major risk factor for nephrolithiasis and oxalate nephropathy. Secondary HO is caused by increased intestinal oxalate absorption from the diet due to enteric disorders or unexplained causes. There are no pharmacologic therapies approved for HO. ALLN-177 is an oral oxalate-specific enzyme therapy (Rx) that degrades oxalate in the gastrointestinal (GI) tract, decreasing oxalate absorption and thereby reducing urine oxalate. ALLN-177’s ability to decrease oxalate burden as assessed by urine and plasma oxalate was tested in a porcine model of HO induced with high oxalate diet (HOD). Pigs were chosen due to physiological similarities to humans in GI and renal function.

Methods

To induce severe HO, 12 pigs were fed HOD for 7 days, followed by a 7-day treatment period continuing on HOD during which a daily oral dose of 22,500 units (u) ALLN-177 was given with feed 3x/day, 7,500 u/meal. HOD was a mix of a regular chow with 2.2 g/kg of Ca, 20% fat and frozen rhubarb (2:1 w/w). The primary endpoint was the within-pig difference in 24h urine oxalate (UOx) on HOD plus ALLN-177 compared to HOD alone, expressed as mg oxalate/g creatinine/24h (mg/gCr/d). Change in plasma oxalate was analyzed, and Oxalobacter colonization was assessed using PCR on fecal samples collected the last day of study treatment with primers designed to detect multiple species of Oxalobacter.

Results

Daily oral ALLN-177 with meals significantly reduced UOx by mean of 38.7 mg/gCr/d (39%) when compared to pre-treatment UOx on HOD (100.1±20.1 vs.: 61.5±14.3 mg/gCr/d on HOD+ALLN-177; p<0.001), returning UOx to the range recorded prior to HOD (61.3 ± 14.5 mg/gCr/d). In addition, mild hyperoxalemia while on HOD (plasma oxalate 13.9±0.9 umol/L) was significantly reduced with Rx to 9.9±2.3 umol/L, p<0.001. PCR of fecal samples was negative for Oxalobacter indicating absence of colonization. Therapy was well tolerated without adverse effects observed.

Conclusion

Orally administered ALLN-177 with meals was well tolerated and normalized UOx and plasma oxalate in a pig model of secondary HO.

Funding

  • Commercial Support