Combination Treatment with Verinurad and Allopurinol in CKD

Abstract

Background: Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia. Methods: In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dL, estimated glomerular filtration rate (eGFR) ≥25 mL/minute/1.73 m2 and a urinary albumin-to-creatinine ratio (UACR) 30-5000 mg/g to one of five treatment arms: placebo, placebo + allopurinol 300 mg/day, verinurad 3 mg + allopurinol 300 mg/day, verinurad 7.5 mg + allopurinol 300 mg/day or verinurad 12 mg + allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary endpoint was the change in UACR from baseline to 34 weeks. Secondary endpoints were changes from baseline in UACR at week 60, and changes in serum urate and eGFR at weeks 34 and 60. Results: Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 mL/min/1.73m2, median UACR 217 mg/g) were enrolled. At 34 weeks; the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7% [95% CI -0.6, 37.1] in the 3 mg group, [15.0% [95%CI -1.85, 34.6] in the 7.5 mg group, 14.0% [95%CI -3.4, 34.4] in the 12 mg group versus 9.9% [95%CI -6.6, 29.4] in the allopurinol group and 37.3% [95%CI 16.6, 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared to placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups. Conclusions: Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared to allopurinol alone or placebo.

Requiem for Urate Lowering in CKD?

“…However, some glowing embers of enthusiasm re-emerged in early 2021 with the publication of the 60-participant CITRINE trial, on the effects of a verinurad and febuxostat combination on albuminuria in patients with type 2 diabetes; this combination therapy reduced albuminuria by approximately 39%. 8 The uricosuric verinurad, developed by Ardea Biosciences and licensed by AstraZeneca, is a highaffinity inhibitor of the apical urate-anion exchanger URAT1. Like its predecessor lesinurad, verinurad monotherapy can be associated with AKI, potentially analogous to the exerciseassociated AKI seen in patients with renal hypouricemia due to loss-of-function mutations in URAT1.…”

“…To follow up on the promising results of CITRINE, AstraZeneca and collaborators designed the Study of ver-inurAd and alloPurinol in Patients with CKD and hyperuricemia trial, the results of which are published in this issue of JASN. 8 Owing to the results of the CARES trial, which suggested an excess of cardiovascular mortality for febuxostat compared with allopurinol, 7 the investigators substituted allopurinol as the xanthine oxidase inhibitor for the Study of verinurAd and alloPurinol in Patients with CKD and hyperuricemia trial. The trial enrolled a total of 861 adults with CKD and eGFR $25 ml/min per 1.73 m 2 , urinary albumin-to-creatinine ratio between 30 and 5000 mg/g, and serum urate $6.0 mg/dl.…”