Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials

Abstract

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan). Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/ NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed. Results: Most patients in study 1 (n ¼ 171) were white (74.9%); all patients were Japanese in study 2 (n ¼ 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and-17.5 ± 2.8,-29.1 ± 2.8,-34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were-2.4 ± 2.5 and-31.7 ± 2.5,-51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo. Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Differential gene expression of ABCG2, SLC22A12, IL-1β and ALPK1 in peripheral blood leukocytes of primary&nbsp;gout&nbsp;patients, was associated to hiperuricemia and their comorbidities. A case control study

“…Studies in human intestinal knockdown cells of ABCG2 stimulated with MSU (Urate monosodium crystal) showed increases in IL-1β and IL8 respectively, therefore this and other studies suggest a relationship between transporters and in ammatory cytokines (14,20). The ALPK1 kinase has been associated with the regulation of the expression of URAT1 and of testosterone in the kidney in murine models (21)(22)(23)(24), therefore, there seems to be an interaction between the expression of in ammatory molecules and the activation of transporters at least in kidney and intestine. Monocytes and neutrophils are important cells in the in ammatory microenvironment of gout and are found in a large percentage in the peripheral blood.…”

“…SLC22A12 is expressed mainly in the luminal membrane of the proximal tubule of the kidney, although it can also be expressed in other tissues such as the liver, brain or in adipocytes (21,24). URAT1 the product of SLC22A12 is important for the reabsorption of uric acid and mutations and polymorphisms of gain of function have been associated with hyperuricemia and gout (39,40).…”

In Vitro Assessment of the Drug–Drug Interaction Potential of Verinurad and Its Metabolites as Substrates and Inhibitors of Metabolizing Enzymes and Drug Transporters

“…Verinurad is a novel, selective inhibitor of URAT1 which was initially studied for the treatment of gout (Shiramoto et al, 2018;Fitz-Patrick et al, 2019;Terkeltaub et al, 2019). Verinurad is currently in development for chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF), in which high levels of uric acid are observed and may constitute either a contributing cause or risk factor for the diseases (Ramirez-Sandoval and Madero, 2018;Sato et al, 2019;Carnicelli et al, 2020a;Carnicelli et al, 2020b).…”

Urate Lowering With Combination Therapy in CKD: Reason for Optimism or Einstein’s Definition of Insanity?

“…Specifically, verinurad, similar to other URAT1 inhibitors, when given without a xanthine oxidase inhibitor has been shown to cause a transient increase in serum creatinine. 12 The exact mechanism behind this observation remains unknown, although it is postulated that this may be due to the microcrystallization of uric acid in the renal tubules as a result of the drug-induced increase in fractional excretion of uric acid. 12 The report by Stack et al shows impressive relative reductions in albuminuria with the combination of febuxostat and verinurad treatment.…”

“…12 The exact mechanism behind this observation remains unknown, although it is postulated that this may be due to the microcrystallization of uric acid in the renal tubules as a result of the drug-induced increase in fractional excretion of uric acid. 12 The report by Stack et al shows impressive relative reductions in albuminuria with the combination of febuxostat and verinurad treatment. Despite recent advances in the management of diabetic kidney disease, 13,14 CKD progression and cardiovascular complications remain.…”