Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: a phase 2a, open-label study

Abstract

ObjectivesVerinurad (RDEA3170) is a high-affinity inhibitor of the URAT1 transporter in clinical development for treating gout and asymptomatic hyperuricaemia. The aim of this Phase 2a, randomized, open-label study was to investigate the multiple-dose pharmacodynamics, pharmacokinetics and safety of oral verinurad combined with febuxostat vs febuxostat alone and verinurad alone.MethodsJapanese male subjects aged 21–65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = 35) and serum urate (sUA) ⩾8 mg/dl were randomized to febuxostat (10, 20, 40 mg) in combination with verinurad (2.5–10 mg), verinurad alone (2.5–15 mg), febuxostat alone (10, 20, 40 mg) or benzbromarone alone (50 mg). There were four treatment periods per cohort and each treatment period was 7 days. Study drugs were administered once-daily after breakfast. Plasma, serum and urine samples were measured at pre-set intervals on days –1, 7, 14, 21 and 28.ResultsVerinurad combined with febuxostat decreased sUA in dose-dependent manner, providing greater sUA lowering than febuxostat alone at the same dose (P < 0.001). Urinary uric acid excretion rate was increased by verinurad, reduced by febuxostat and comparable to baseline for verinurad combined with febuxostat. Verinurad from 2.5 mg to 15 mg was well tolerated, with no withdrawals due to adverse events. Laboratory assessments showed no clinically meaningful changes during combination treatment.ConclusionVerinurad combined with febuxostat decreased sUA dose-dependently while maintaining uric acid excretion similar to baseline. All dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov, NCT02317861

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

“…The results of this trial further the concept that potent URAT1 inhibitors without prolonged activities in humans, such as lesinurad and verinurad, must be given with an XOI that simultaneously reduces the production of uric acid. To this end, no subjects in the trials where verinurad was combined with an XOI have shown increases in sCr !1.5 Â baseline [24][25][26]. These results are consistent with those of lesinurad, which is associated with significant increases in renal AEs when given as monotherapy [10].…”

“…A patient on benzbromarone excretes uric acid at a lower steady rate over the entire 24-hour period post dosing whereas a patient on verinurad excretes uric acid at a higher rate over the initial 6-8 hours. The higher rate of excretion with verinurad was reduced to less than or equal to that with benzbromarone when combined with an XOI [24].…”

“…Its use is generally considered to not be associated with renal AEs, although no large wellcontrolled studies with frequent sCR monitoring are available. When benzbromarone and verinurad were compared in a head-to-head study, benzbromarone demonstrated a lower maximum rate of uric acid excretion compared with verinurad [24]. This is important because we believe that the maximal rate of uric acid excretion correlates with risk for a renal AE, as too much uric acid in the renal tubule at one time leads to saturation and precipitation of uric acid (uric acid nephropathy).…”

“…However, the possibility that excessive uric acid excretion is associated with nephropathy may mean that verinurad should be administered with an agent that reduces uric acid production and minimizes uric acid in the kidney. The combination of verinurad with an XOI has been successfully studied elsewhere [24][25][26].…”

Clinical study of different doses of atorvastatin combined with febuxostat in patients with gout and carotid atherosclerosis

“…Gout is a type of acute and chronic inflammation and tissue damage caused by the deposition of monosodium urate in bone joints, kidneys and subcutaneous areas, and it is directly related to hyperuricemia caused by purine metabolic disorder and/or reduced uric acid excretion. 6 During an acute attack, the main manifestations were inflammation, joint swelling, heat and pain and were usually relieved spontaneously within two weeks. After that, the patient has entered the intermission period between attacks, which is characterized by asymptomatic hyperuricemia.…”