Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with febuxostat in adults with gout: a phase IIa, open-label study

Roy Fleischmann, Peter Winkle, Jesse Hall, Shakti Valdez, Sha Liu, Xiaohong Yan, Liz Hicks, Caroline Lee, Jeffrey N Miner, Michael Gillen, Martha Hernandez-Illas, Roy Fleischmann, Peter Winkle, Jesse Hall, Shakti Valdez, Sha Liu, Xiaohong Yan, Liz Hicks, Caroline Lee, Jeffrey N Miner, Michael Gillen, Martha Hernandez-Illas

Abstract

Objective: Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for treating gout and asymptomatic hyperuricaemia. This study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad in combination with febuxostat in adults with gout.

Methods: The phase IIa, open-label, multicentre study randomised 64 subjects into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in combination with verinurad 2.5-20 mg. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events, chemistry panels, ECGs and physical examinations.

Results: Serum pharmacodynamic data demonstrated the maximum percent decrease in serum urate (sUA) from baseline (Emax) at 8-12 hours after dosing. Verinurad with febuxostat decreased sUA in a dose-dependent manner. Emax for verinurad with febuxostat 40 mg ranged from 52% to 77% vs 42% for febuxostat 40 mg alone; Emax for verinurad with febuxostat 80 mg was 62%-82% vs 55% for febuxostat 80 mg alone. Urinary uric acid excretion rate was reduced below baseline by febuxostat alone and was comparable to baseline for verinurad with febuxostat. Verinurad plasma exposure increased with dose and was comparable when combined with febuxostat. No drug-drug interactions were observed. Verinurad was well tolerated with no clinically meaningful changes in laboratory values.

Conclusion: Verinurad administered with febuxostat produced dose-dependent decreases in sUA while maintaining urinary uric acid levels comparable to baseline. These dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout.

Trial registration number: NCT02246673.

Keywords: febuxostat; gout; verinurad.

Conflict of interest statement

Competing interests: RF received a clinical study grant from Ardea Biosciences. PW is a full-time employee of Anaheim Clinical Trials. JH, SV, SL, XY, LH, CL and JNM are/were full-time employees of Ardea Biosciences, a member of the AstraZeneca Group at the time of this study. MG is a full-time employee of AstraZeneca.

Figures

Figure 1
Figure 1
Study design. Febuxostat dose 40 or 80 mg; verinurad dose range 2.5–20 mg.
Figure 2
Figure 2
Mean (SE) percent change from baseline in sUA (µmol/L) following oral doses of febuxostat 40 mg (top) or 80 mg (bottom) in combination with varying doses of verinurad vs febuxostat 40 or 80 mg alone (overall treatment pooled across cohorts) (PD population. Patient n in parentheses: top (febuxostat 40 mg): febuxostat alone (60), verinurad 2.5 mg (12), verinurad 5 mg (12), verinurad 10 mg (24), verinurad 15 mg (23), verinurad 20 mg (11); bottom (febuxostat 80 mg): febuxostat alone (48), verinurad 2.5 mg (12), verinurad 5 mg (12), verinurad 10 mg (11), verinurad 15 mg (12)). PD, pharmacodynamics.
Figure 3
Figure 3
Mean (SE) maximum urinary uric acid excretion rate (mg/hour) following verinurad doses in combination with febuxostat 40 or 80 mg vs febuxostat 40 or 80 mg alone (pharmacodynamics population, pooled across cohorts. Patient n: see figure 2).

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