Abstract
Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.
Highlights
Hyperuricemia, defined as a serum urate concentration greater than either 6.8 or 7.0 mg/dl [1], affects around 20% of adults within the United States [2] and promotes the development of gout, which in the United States has a prevalence of ∼4%
Our work demonstrates that oral treatment with ALLN-346 reduces both hyperuricemia and hyperuricosuria in URKO mice via effective degradation of urate secreted in the intestinal tract
Removal of allopurinol from the drinking water in the 7-day study resulted in severe hyperuricemia and hyperuricosuria with mean values of plasma and urine urate of 14.01 ± 0.86 mg/dl and 5.03 ± 0.35 mg/24 h, respectively
Summary
Hyperuricemia, defined as a serum urate (sUA) concentration greater than either 6.8 or 7.0 mg/dl [1], affects around 20% of adults within the United States [2] and promotes the development of gout, which in the United States has a prevalence of ∼4%. Urolithiasis is common in gout and is promoted by decreased solubility of uric acid in the acidic pH of the urine and increased urinary uric acid concentration [4]. Gout is associated with a decreased health-related quality of life and increased health care utilization [5]. Hyperuricemia has been identified as a potential contributor to the pathophysiology of multiple comorbidities associated with gout, and with asymptomatic hyperuricemia. These include hypertension, chronic kidney disease (CKD), obesity, metabolic syndrome, type 2 diabetes, and coronary artery disease [6,7,8,9]
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