Date: Monday, October 22, 2018
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
A novel recombinant oral urate oxidase (UrOx) ALLN-346 reduces severe hyperuricemia and normalizes hyperuricosuria in nephropathic UrOx knockout (UrOxKO) mice
Background/Purpose: Limitations in efficacy and/or tolerance of oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to refractoriness to urate-lowering therapy (ULT) in gout. Renal excretion is the major route of uric acid elimination, but the gastrointestinal tract (GIT) plays an increasingly recognized role in urate homeostasis, especially in chronic kidney disease (CKD) where urate renal elimination is impaired. Here, we targeted gut elimination of urate in vivo with ALLN-346, an orally administered, engineered UrOx optimized for proteolytic stability in the GIT. We tested ALLN-346 in UrOxKO mice, with severe hyperuricemia, hyperuricosuria and uric acid crystalline obstructive nephropathy.
Methods: This was a parallel 21-day study of 3 periods (pre-treatment, treatment and follow up, each 7d) and 3 arms, ALLN-346 mixed with food (150 mg/day, n=8) compared to allopurinol (ALLO) doses of 150 mg/L (n=9) and 50 mg/L (n=8) supplemented in water. During the pre-treatment period, the maintenance dose of ALLO (150 mg/L) was removed. Plasma urate was measured in samples collected on the last day of each study period, and uric acid was measured in 24-hour urine samples collected during the last 3 days of pre-treatment and treatment periods (Cormay Liquick Cor-UA 30 plus, PL).
Results: Hyperuricemia was reduced significantly (p<0.001) and hyperuricosuria normalized with 7 days ALLN-346 oral therapy (Figure 1). On ALLN-346, mean (SEM) plasma urate decreased by 44% from pre-treatment (14.5±0.9 to 8.1±0.5 mg/dL), similar to 51% in the 50 mg ALLO group (13.2±2.6 to 6.5±1.1 mg/dL); p=NS. The highest reduction of 69% was in the ALLO 150 arm (13.8±1.7 to 4.3±0.6 mg/dL). Urine urate excretion normalized (<2mg/24h) with ALLN-346, mean (SEM) reduction was 86% (4.7±0.6 to 0.7±0.1mg/24h); while in ALLO 50 and 150 arms reduction was 34% (4.9±0.4 to 3.2±0.3mg/24h) and 66% (6.4±0.7 to 2.2±0.3mg/24h) respectively. Removal of ALLN-346 or ALLO in follow up resulted in hyperuricemia returning to approximately pre-treatment levels. Analysis of chyme from different GIT segments indicated the urate presence along the whole gut.
Conclusion: Novel targeting of enteric uric acid by oral ALLN-346 therapy successfully lowered serum urate and normalized urinary uric acid in nephropathic UrOxKO mice. Enhanced elimination of urate via degradation in the GIT could be an effective addition to pharmacologic ULT and supports rationale for testing ALLN-346 in humans with gout and hyperuricemia, particularly in CKD.
To cite this abstract in AMA style:Grujic D, Desphande A, Terkeltaub R, Mosiichuk N, Goncharva K, Pirzynowski S. A Novel Recombinant Oral Urate Oxidase (UrOx) Alln-346 Reduces Severe Hyperuricemia and Normalizes Hyperuricosuria in Nephropathic Urox Knockout (UrOxKO) Mice [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/a-novel-recombinant-oral-urate-oxidase-urox-alln-346-reduces-severe-hyperuricemia-and-normalizes-hyperuricosuria-in-nephropathic-urox-knockout-uroxko-mice/. Accessed October 30, 2020.
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