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 = 171) were white (74.9%); all patients were Japanese in study 2 (n = 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.

Keywords:

• Asymptomatic hyperuricemia
• gout
• selective uric acid reabsorption inhibitor
• serum urate
• verinurad

1. Introduction

Gout is a serious, chronic, and debilitating disease caused by high levels of serum urate (sUA; hyperuricemia); in approximately 90% of patients, hyperuricemia is the result of inadequate uric acid excretion [1], while a small percentage of patients overproduce uric acid. Hyperuricemia leads to the formation and deposition of monosodium urate crystals in the tissues of the body, particularly in and around the joints [2]. If not appropriately treated, gout may progress to a chronic and disabling disease resulting in disfiguring tophi, joint destruction, and persistent pain [2–4].

Maintenance of sUA levels below 6.0 mg/dL (below 5.0 mg/dL for greater disease severity) with urate-lowering therapy (ULT), along with lifestyle changes, is recommended for long-term management of gout [4]. Xanthine oxidase inhibitors (XOIs), such as allopurinol or febuxostat, that reduce the production of urate to lower sUA, are the recommended first line of ULT [4–6]. If desired sUA levels cannot be reached or maintained with an XOI, treatment guidelines recommend combination therapy that includes an XOI with a uric acid reabsorption inhibitor [4–6]. Guidelines in Japan recommend that patients with hyperuricemia, but without gout, start drug therapy if their sUA is ≥8.0 mg/dL and they have ≥1 comorbidities (hypertension, diabetes, etc.) or if their sUA is ≥9.0 mg/dL and no complications [7,8].

The uricosurics, probenecid, benzbromarone, sulfinpyrazone, and lesinurad increase renal excretion of uric acid by inhibiting its reabsorption [9]. Lesinurad, a selective uric acid reabsorption inhibitor, was recently approved at a dose of 200 mg in the USA and Europe in combination with an XOI for the treatment of hyperuricemia associated with gout in patients who fail to achieve target sUA levels on an XOI alone. In the Phase III clinical development program, lesinurad 400 mg reduced sUA levels but had a high rate of renal-related adverse effects [10]. Treatment with lesinurad 200 mg and 400 mg in combination with allopurinol or febuxostat resulted in lower sUA levels, more patients achieving target sUA than with an XOI alone, and a rate of renal-related adverse events (AEs) with lesinurad 200 mg that was similar to an XOI alone [11–13].When patients with tophaceous gout were treated with lesinurad + febuxostat, more patients experienced reduction in overall tophus area compared with febuxostat alone [12]. However, this treatment combination only showed trends toward reductions in gout flares at the 400 mg dose, a dose that had increased renal side effects compared with lesinurad 200 mg + febuxostat and febuxostat alone. Lesinurad 400 mg was neither submitted to nor approved by US and European regulatory agencies.

The clinical trial experience with urate-lowering agents has demonstrated that achieving sUA levels below recommended targets may lead to improved outcomes (e.g., lower gout flare incidence, more rapid tophus area reduction, etc.) [14–18].

Verinurad, a selective URAT1 inhibitor, demonstrated high potency in inhibiting URAT1 [19] and has shown significant sUA lowering in humans at doses as low as 2.5 mg [20]. Recent studies with verinurad have provided favorable safety, pharmacokinetic (PK), and pharmacodynamic data when the drug is administered alone to healthy male non-Asian or Japanese patients [21]. Here we report the results of two randomized, double-blind, multicenter, placebo-controlled, 24-week Phase II studies that evaluated the efficacy and safety of verinurad monotherapy in Western patients with gout or Japanese patients with asymptomatic hyperuricemia or gout.

2. Methods

2.1. Patients

In study 1, male or female (post-menopausal or surgically sterile) patients aged ≥18 and ≤70 years who were diagnosed with gout (based on the American Rheumatism Association criteria for the classification of acute arthritis of primary gout [22]) and who had sUA levels ≥6.5 mg/dL and ≤10.0 mg/dL during the screening period and a body mass index <40 kg/m² were eligible for inclusion. Patients were excluded if they had sUA >10 mg/dL.

In study 2, male or female (post-menopausal or surgically sterile) Japanese patients aged ≥20 and ≤70 years who had sUA levels ≤10.0 mg/dL and who met any of the following criteria, based on the Japanese Guidelines for management of hyperuricemia and gout [7], 7 days prior to baseline were eligible for inclusion: (1) sUA levels >7.0 mg/dL with gout; (2) sUA levels ≥8.0 mg/dL without gout but with comorbidities (hypertension, ischemic heart disease, diabetes, metabolic syndrome); (3) sUA levels ≥9.0 mg/dL without gout and complications. Exclusion criteria included patients with body mass index ≥40 kg/m², an acute gout flare that had not resolved at least 14 days prior to the baseline visit, an estimated creatinine clearance rate (eCrCl) <60 mL/min, or a history or suspicion of kidney stones.

2.2. Study design

Both studies were Phase II, randomized, double-blind, multicenter, placebo-controlled studies to evaluate the efficacy and safety of verinurad monotherapy in patients with gout (study 1; NCT01927198) or patients with gout or asymptomatic hyperuricemia (study 2; NCT02078219). Study 1 was conducted at 46 sites in the United States and consisted of a 7- to 21-day screening period, followed by a 24-week double-blind treatment period, and a 14-day follow-up period (Figure 1(A)). Subjects on ULT discontinued their ULT and began 0.6 mg colchicine as gout prophylaxis on day −21, while those not taking ULT began colchicine at randomization on day 0 (baseline). Patients were randomized 1:1:1:1 to one of four treatment groups: Placebo for 24 weeks; Verinurad group 1: 5 mg once a day (qd) for 24 weeks; Verinurad group 2: 5 mg qd for 2 weeks then 10 mg qd for 22 weeks; and Verinurad group 3: 5 mg qd for 2 weeks, 10 mg qd for 2 weeks, followed by 12.5 mg qd for 20 weeks. Patients returned to the study site at weeks 1, 2, 4, 6, and 8, and then every 4 weeks thereafter through week 24. All subjects completed a follow-up visit 2 weeks after the last dose of study medication.

Figure 1. Study design for study 1 (a) and study 2 (b).

Study 2 was conducted at 14 centers in Japan and consisted of a 4-week screening period, followed by a 24-week double-blind treatment period, and a 14-day follow-up period (Figure 1(B)). Patients were randomized 1:1:1:1:1 to one of five treatment groups: Placebo: placebo qd for 24 weeks; Verinurad group 1: 2.5 mg qd for 4 weeks followed by 5 mg qd for 12 weeks followed by verinurad 7.5 mg qd for 8 weeks; Verinurad group 2: 2.5 mg qd for 4 weeks followed by 5 mg qd for 4 weeks followed by verinurad 10 mg qd for 8 weeks followed by 12.5 mg qd for 8 weeks; Verinurad group 3: 2.5 mg qd for 4 weeks followed by 5 mg qd for 4 weeks followed by verinurad 12.5 mg qd for 8 weeks followed by 15 mg qd for 8 weeks; and Allopurinol: allopurinol 100 mg qd for 4 weeks followed by twice-daily allopurinol 100 mg (total daily dose 200 mg) for 20 weeks. Patients were evaluated weekly for the first 2 weeks, then bi-weekly for the rest of the treatment period, and returned for the end-of-study visit 2 weeks after the final dose of study medication.

Study protocols were reviewed and approved by the institutional review board and/or independent ethics committee at each site, and the studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation/Good Clinical Practice. All patients provided written informed consent before participation.

2.3. Study objectives and endpoints

The primary objective was to compare the efficacy of verinurad monotherapy with placebo at week 12 (study 1) or week 16 (study 2). Secondary objectives included evaluating the efficacy and safety of verinurad monotherapy compared with placebo over 24 weeks (study 1 and study 2). The PK objective was to characterize verinurad exposure in patients from both studies. The primary efficacy endpoint was the percentage change from baseline in sUA levels at week 12 (study 1) or week 16 (study 2). Secondary efficacy endpoints included: (1) the percentage change from baseline in sUA levels at each visit (week) and; (2) the proportion of patients with sUA <6.0 mg/dL and sUA <5.0 mg/dL (study 1) and sUA ≤6.0 mg/dL (study 2) at each visit (week). Safety endpoints for both studies included AEs and laboratory investigations.

2.4. Study assessments

Blood samples for sUA measurements were collected throughout the study, while sparse blood samples for PK analysis were collected at week 12 and 24 (study 1) and weeks 16 and 24 (study 2). The plasma PK samples were extracted by protein precipitation and verinurad quantified by Ardea Biosciences, Inc. (San Diego, CA, USA) using liquid chromatography tandem mass spectrometry as previously described [20]. The calibration curves for both studies were linear over the concentration range between 0.1 ng/mL and 40 ng/mL, with a lower limit of quantitation of 0.1 ng/mL and precision (CV%) that varied between 2.6 and 5.4% in study 1 and between 2.5 and 4.5% in study 2.

Subjects were observed throughout the study and any AEs or remedial actions were documented in the patient’s clinical report form. Rheumatology Common Toxicity Criteria (RCTC) version 2.0 was used by the investigator to assess the severity of an AE. AEs were defined as serious if they resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization, or caused persistent or significant disability/incapacity. Clinical laboratory evaluations, supine blood pressure, pulse rate, respiratory rate, and oral body temperature were measured at specific times during the study. A physical examination and standard digital 12-lead electrocardiograms (ECGs) were recorded at screening and follow-up.

Renal safety was of particular interest because verinurad increases excretion of urinary uric acid and thereby increases the potential for microcrystallization of uric acid in the renal tubules, uric acid calculi, and acute uric acid nephropathy [23]. All treatment-emergent AEs (TEAEs) preferred terms (PTs) mapping to the MedDRA Acute Renal Failure Standard Medical Query (SMQ) version 14.0 were reviewed. Laboratory abnormalities (e.g., serum creatinine [sCr] elevations) were only classified as TEAEs if they were considered by the investigator to be clinically significant. Any associated clinical diagnosis (e.g., renal impairment, acute renal failure) was provided by the investigator. Severity was determined by the investigator according to the Rheumatology Common Terminology Criteria for Adverse Events (CTCAE), as was the relationship to study drug. The PTs that comprise the Acute Renal Failure SMQ are listed in Supplemental Material Table 1.

2.5. Statistical analysis and sample size determination

The intent-to-treat population (study 1), efficacy population (study 2), and safety population (studies 1 and 2) included all randomized patients who received at least one dose of randomized study medication. The PK population included all patients who received at least one dose of randomized study medication and had evaluable PK data. All analyses used SAS® version 9.1.3 (SAS Institute Inc., Cary, NC, USA) or higher. The primary and secondary efficacy endpoints were summarized using descriptive statistics.

Results of the primary endpoint in both studies were analyzed using an analysis of covariance (ANCOVA) model with treatment group as fixed effect. In study 1, the model was adjusted for baseline sUA and tophus status (absence or presence) during the screening period, while in study 2, the model included gout (absence or presence), and type of hyperuricemia as fixed effect and the baseline value as a covariate. The last observation carried forward (LOCF) method was used in both studies for patients missing the sUA result at study endpoint.

Results of the proportion of patients with sUA <6.0 and <5.0 mg/dL at each visit (week) in study 1 were summarized by treatment group. The difference of the response rates between each verinurad group and the placebo group were compared using the Cochran-Mantel-Haenszel test, stratified by tophus status during the screening period. A nonresponder imputation (NRI) was used for all visits (week), where any patient who was missing a response at a particular visit (week) for any reason was considered a nonresponder at that visit (week). The proportion of patients who achieved sUA ≤6.0 mg/dL at each visit (week) in study 2 was summarized for each treatment group, using the NRI method for missing data.

The sample size for both studies was calculated to give approximately 90% power to show that at least one of the three verinurad dose groups had a statistically significant difference compared with placebo, testing at the overall two-sided α 5% level. Dunnett's method was used to adjust for multiplicity (study 2). The calculation was based on the assumption of a treatment difference of 18 between verinurad and placebo in percentage change from baseline to week 12 (study 1) or week 16 (study 2) in the sUA level and a common SD of 21. Forty patients were also included in an allopurinol group as a benchmark in study 2.

3. Results

3.1. Patients

In study 1, 171 of 172 randomized patients received at least one dose of randomized study medication. Forty-two patients received placebo, 42 received verinurad in group 1, 43 in group 2, and 44 in group 3. In study 2, all 204 randomized patients received at least one dose of randomized study medication. Forty patients received placebo, 41 each received verinurad in groups 1–3, and 41 received allopurinol. Twenty-nine patients (17.0%) in study 1 and 19 patients (9.3%) in study 2 withdrew from the study early (Supplemental Material Table 2).

Most patients in both studies were male (Table 1). The majority of patients in study 1 were white, whereas all were Japanese in study 2. Mean age was 53.7 years in study 1 and 52.3 years in study 2. Mean body mass index was 31.9 kg/m² and 26.0 kg/m², respectively; time since gout diagnosis was 11.1 (8. 7) years and 6.9 (7.6) years, respectively. All patients in study 1 had gout, while 53.9% had gout and 46.1% had asymptomatic hyperuricemia in study 2. Most patients in both studies had an eCrCl ≥ 60 mL/min. The most frequently reported comorbidities in study 1 were hypertension (55.0%) and hypercholesterolemia (47.4%), while in study 2 they were hypertension (54.4%) and hypertriglyceridemia (39.4%). Overall, demographic and baseline characteristics were similar across the treatment groups in each study.

Table 1. Demographic/baseline characteristics of patients in study 1 and study 2.

	Study 1			Study 2
Variable	Placebo (n = 42)	Verinurad pooled (n = 129)	Total (N = 171)	Placebo (n = 40)	Verinurad pooled (n = 123)	Allopurinol 100 mg (n = 41)	Total (N = 204)
Age, years, mean (SD)	55.0 (9.53)	53.3 (9.44)	53.7 (9.5)	54.5 (10.3)	52.1 (9.9)	51.0 (10.6)	52.3 (10.2)
Age group, n (%)
<65 years	34 (81.0)	114 (88.4)	148 (86.5)	29 (72.5)	106 (86.2)	36 (87.8)	171 (83.8)
≥ 65 years	8 (19.0)	15 (11.6)	23 (13.5)	11 (27.5)	17 (13.8)	5 (12.2)	33 (16.2)
Sex, Male, n (%)	39 (92.9)	120 (93.0)	159 (93.0)	39 (97.5)	120 (97.6)	41 (100.0)	200 (98.0)
Race, n (%)
American Indian/Alaska Native	1 (2.4)	1 (0.8)	2 (1.2)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Asian	1 (2.4)	7 (5.4)	8 (4.7)	40 (100.0)	123 (100.0)	41 (100.0)	204 (100.0)
Black/African American	7 (16.7)	17 (13.2)	24 (14.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Native Hawaiian/otherPacific Islander	2 (4.8)	2 (1.6)	4 (2.3)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
White	31 (73.8)	97 (75.2)	128 (74.9)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Other	0 (0)	5 (3.9)	5 (2.9)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Ethnicity, n (%)
Hispanic or Latino	4 (9.5)	8 (6.2)	12 (7.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Not Hispanic or Latino	38 (90.5)	121 (93.8)	159 (93.0)	40 (100.0)	123 (100.0)	41 (100.0)	204 (100.0)
Body weight, kg, mean (SD)	102.9 (19.4)	100.1 (18.3)	100.8 (18.6)	77.0 (14.4)	75.9 (10.3)	73.2 (11.9)	75.6 (11.6)
Body mass index, kg/m^2, mean (SD)	32.3 (4.9)	31.8 (4.7)	31.9 (4.7)	26.6 (4.4)	26.1 (3.0)	25.1 (3.2)	26.0 (3.4)
Type of gout-related primary disease, n (%)
Gout	42 (100.0)	129 (100.0)	171 (100.0)	21 (52.5)	67 (54.5)	22 (53.7)	110 (53.9)
Asymptomatic hyperuricemia	0 (0.0)	0 (0.0)	0 (0.0)	19 (47.5)	56 (45.5)	19 (46.3)	94 (46.1)
Duration since gout diagnosis, years, mean (SD)	12.7 (10.2)	10.5 (8.1)	11.1 (8.7)	8.2 (8.2)	6.7 (7.6)	6.3 (6.8)	6.9 (7.6)
Renal function at baseline, mL/min, n (%)
eCrCl ≥90	20 (47.6)	59 (45.7)	79 (46.2)	28 (70.0)	87 (70.7)	32 (78.0)	147 (72.1)
eCrCl 60–<90	20 (47.6)	66 (51.2)	86 (50.3)	10 (25.0)	35 (28.5)	8 (19.5)	53 (26.0)
eCrCl <60	2 (4.8)	4 (3.1)	6 (3.5)	2 (5.0)	1 (0.8)	1 (2.4)	4 (2.0)
Serum urate, mg/dL, mean (SD)	8.73 (0.93)	8.73 (0.93)	8.56 (1.29)	8.59 (0.98)	8.43 (0.99)	8.72 (1.00)	8.52 (0.99)

eCrCl: estimated creatinine clearance; SD: standard deviation.

3.2. Efficacy

The least-squares (LS) means estimate of the percentage change (reduction) in sUA levels from baseline at week 12 in study 1 and at week 16 in study 2 increased in a dose-dependent manner (Figure 2(A) and Table 2). The difference in LS means versus placebo was statistically significant for all three verinurad doses (p < .0001 each) in both studies (Table 2). In study 2, the difference in LS means versus allopurinol 100 mg twice daily was significant for verinurad 10 mg (p = .0003) and verinurad 12.5 mg (p < .0001) but significant for allopurinol with verinurad 5 mg (p = .0244) (Table 2).

Figure 2. Estimated mean (SE) change from baseline in sUA at week 12 in study 1 and at week 16 in study 2 (a) and percentage of patients with sUA <6.0 and <5.0 mg/dL at week 12 in study 1 and percentage of patients with sUA ≤6.0 at week 16 in study 2 (b) as a function of verinurad dose. Results with allopurinol 100 mg twice a day (bid) in study 2 are also shown. The verinurad dose at week 12 or week 16 represents the dose at that week. In study 1, 5 mg dose was given for all 12 weeks; 10 mg dose was 5 mg for 2 weeks and 10 mg for 10 weeks; 12.5 mg dose was 5 mg for 2 weeks, 10 mg for 2 weeks and 12.5 mg for 8 weeks. In study 2, 5 mg dose was 2.5 mg for 4 weeks and 5 mg for 12 weeks; 10 mg dose was 2.5 mg for 4 weeks, 5 mg for 4 weeks, and 10 mg for 8 weeks; 12.5 mg dose was 2.5 mg for 4 weeks, 5 mg for 4 weeks, and 12.5 mg for 8 weeks. Allopurinol 100 mg was given once daily for 4 weeks and 100 mg twice daily for 12 weeks. In study 1, % change from baseline in sUA was analyzed by ANCOVA with baseline sUA and tophus status (absence/presence) during screening as covariates and treatment group as fixed effect. Proportion of patients with sUA <6.0 mg/dL or <5.0 mg/dL was analyzed by Cochran-Mantel-Haenszel statistic stratified by tophus status (absence/presence) during screen and using nonresponder imputation. In study 2, % change from baseline in sUA was analyzed by ANCOVA with treatment group, gout (absence/presence) and type of hyperuricemia as fixed effects and baseline sUA as a covariate. Proportion of patients with sUA ≤6.0 mg/dL was summarized by treatment group where missing data was imputed using nonresponder imputation. ANCOVA: analysis of variance; sUA: serum urate.

Table 2. Analysis of the percentage change from baseline in sUA (primary endpoint) at week 12 (study 1, ITT population) and week 16 (study 2, efficacy analysis set) – LOCF imputation.

	PBO	Verinurad 5 mg	Verinurad 10 mg	Verinurad 12.5 mg
Study 1 – week 12
Estimated LS mean (SE) change from baseline in sUA, %	1.2 (2.9)	–17.5 (2.8)	–29.1 (2.8)	–34.4 (2.9)
Adjusted mean difference vs PBO (95% CI)	–	–18.70 (–25.90, –11.49)	–30.37 (–37.55, –23.19)	–35.58 (–42.73, –28.44)
p value		< .0001	< .0001	< .0001
Study 2 – Week 16: verinurad vs PBO
Estimated LS mean (SE) change from baseline in sUA, %	–2.4 (2.5)	–31.7 (2.5)	–51.7 (2.6)	–55.8 (2.5)
LS mean difference vs PBO (95% CI)	–	–29.28 (–36.99, –21.57)	–49.25 (–56.97, –41.52)	–53.33 (–61.00, –45.67)
p value		< .0001	< .0001	< .0001
Study 2 – Week 16: verinurad vs allopurinol
	Allopurinol	Verinurad 5 mg	Verinurad 10 mg	Verinurad 12.5 mg
Estimated LS mean (SE) change from baseline in sUA, %	–38.99 (2.60)	–31.36 (2.54)	–51.29 (2.70)	–55.42 (2.55)
LS mean difference vs PBO (95% CI)	–	7.63 (1.00, 14.26)	–12.30 (–18.88, –5.72)	–16.43 (–23.00, –9.86)
p value		.0244	.0003	< .0001

The verinurad dose at week 12 or week 16 represents the dose at that week. In study 1, 5 mg dose was given for all 12 weeks; 10 mg dose was 5 mg for 2 weeks and 10 mg for 10 weeks; 12.5 mg dose was 5 mg for 2 weeks, 10 mg for 2 weeks and 12.5 mg for 8 weeks. In study 2, 5 mg dose was 2.5 mg for 4 weeks and 5 mg for 12 weeks; 10 mg dose was 2.5 mg for 4 weeks, 5 mg for 4 weeks, and 10 mg for 8 weeks; 12.5 mg dose was 2.5 mg for 4 weeks, 5 mg for 4 weeks, and 12.5 mg for 8 weeks. Allopurinol was 100 mg once daily for 4 weeks and 100 mg twice daily for 12 weeks.

In study 1, % change from baseline in sUA was analyzed by ANCOVA with baseline sUA and tophus status (absence/presence) during screening as covariates and treatment group as fixed effect. In study 2, % change from baseline in sUA was analyzed by ANCOVA with treatment group, gout (absence/presence) and type of hyperuricemia as fixed effects and baseline sUA as a covariate.

ANCOVA: analysis of variance; CI: confidence interval; ITT: intent to treat; LOCF: last observation carried forward; LS: least squares; PBO: placebo; sUA: serum urate.

The dose-dependent decrease in sUA was accompanied by a dose-dependent increase in the proportion of patients with sUA <6.0 mg/dL or <5.0 mg/dL at week 12 in study 1 and with sUA ≤6.0 mg/dL at week 16 in study 2 (Figure 2(B)). The proportion of patients in study 1 with sUA <6.0 mg/dL was significantly greater with verinurad 5 mg, 10 mg, and 12.5 mg compared with placebo in both study 1 (p = .0025, p < .0001, and p < .0001, respectively) and study 2 (p = .0011, p < .0001 and p < .0001, respectively). The proportion of patients with sUA <5.0 mg/dL in study 1 was statistically greater for the 10 mg and 12.5 mg doses (p = .0020 and p < .0001, respectively). When verinurad was compared with allopurinol 100 mg twice daily for the proportion of patients with sUA ≤6.0 mg/dL in study 2, verinurad 12.5 mg was statistically superior to allopurinol with an estimated odds ratio of patients with sUA ≤6.0 mg/dL (95% confidence interval) of 9.36 (1.07; 81.58); p = .0429. Verinurad 10 mg was not superior to allopurinol (4.56 [0.85; 24.32]; p = .0760), while allopurinol was statistically superior to verinurad 7.5 mg (0.18 [0.06; 0.57]; p = .0033).

In study 1, a significant treatment effect of verinurad was observed at all study visits for the mean percentage change from baseline in sUA levels (Figure 3(A); p < .001 for each visit) and for the proportion of patients with sUA <6.0 mg/dL (Figure 3(B); significance ranging from p < .001 top = .0058), including week 1 and week 2 when patients in all the verinurad groups were receiving verinurad 5 mg daily. Following up-titration of the verinurad dose to 10 mg for groups 2 and 3 at the beginning of week 3, a dose-response effect was observed as early as week 4 for these two groups compared with the verinurad 5 mg dose group. Similar results were observed in study 2 where a dose-response effect was observed beginning with the up-titration from 5 mg at the beginning at week 9 and continuing with the further up-titration at the beginning of week 17 (Figure 3(C), 3(D)).

Figure 3. Estimated mean (SE) percentage change from baseline in sUA (panels a and c) and proportion of patients with sUA <6.0 mg/dL (panel b) and sUA ≤6.0 mg/dL (panel d) by visit in study 1 (panels a and b) and in study 2 (panels c and d). (Panel a) Intent-to treat population (observed cases); (Panel b) Intent-to-treat population (NRI; observed cases); (Panels c and d) efficacy population (LOCF). In study 1, verinurad group 1 received 5 mg daily for 24 weeks. Group 2 received 5 mg for 2 weeks and 10 mg for 22 weeks. Group 3 received 5 mg for 2 weeks; 10 mg for 2 weeks; and 12.5 mg for 20 weeks. In study 2, verinurad group 1 received 2.5 mg daily for 4 weeks; 5 mg daily for 12 weeks; and 7.5 mg for 8 weeks. Group 2 received 2.5 mg daily for 4 weeks; 5 mg for 4 weeks; 10 mg for 8 weeks; and 12.5 mg for 8 weeks. Group 3 received 2.5 mg for 4 weeks; 5 mg for 4 weeks; 12.5 mg for 8 weeks; and 15 mg for 8 weeks. The allopurinol group received 100 mg daily for 4 weeks and 100 mg twice a day for 20 weeks. LOCF: last observation carried forward; NRI: nonresponder imputation.

Figure 4 summarizes the results at week 24 where the dose-dependent change (reduction) in sUA levels and increased proportions of patients at target sUA levels at week 12 were maintained in study 1. In study 2, the verinurad dose was increased at the start of week 17 from 5 mg to 7.5 mg in group 1, from 10 mg to 12.5 mg in group 2, and from 12.5 mg to 15 mg in group 3. At week 24, there was a dose-dependent change (reduction) from baseline in sUA (Figure 4(A)) and a dose-dependent increase in the proportion of patients with sUA ≤6.0 mg/dL (Figure 4(B)). The mean percentage change from baseline in sUA and the proportion of patients with sUA ≤6.0 mg/dL with allopurinol 100 mg twice daily at week 16 was also maintained at week 24. The percentage change from baseline in sUA and the proportion of patients with sUA ≤6.0 mg/dL was generally similar throughout study 2 for patients with gout and those with asymptomatic hyperuricemia.

Figure 4. Change from baseline in sUA and percentage of patients with sUA <6.0 and <5.0 mg/dL at week 24 in study 1 (a) and change from baseline in sUA and percentage of patients with sUA ≤6.0 at week 24 in study 2 (b) as a function of verinurad dose at week 24. Results with allopurinol (ALLO) 100 mg twice daily in study 2 are also shown in panels b and d. The verinurad dose at week 24 represents the dose at that week. In study 1, 5 mg dose was given for all 24 weeks; 10 mg dose was 5 mg for 2 weeks and 10 mg for 22 weeks; 12.5 mg dose was 5 mg for 2 weeks, 10 mg for 2 weeks and 12.5 mg for 20 weeks. In study 2, 7.5 mg dose was 2.5 mg for 4 weeks, 5 mg for 12 weeks, and 7.5 mg for 8 weeks; 12.5 mg dose was 2.5 mg for 4 weeks, 5 mg for 4 weeks, 10 mg for 8 weeks, and 12.5 mg for 8 weeks; 15 mg dose was 2.5 mg for 4 weeks, 5 mg for 4 weeks, 12.5 mg for 8 weeks, and 15 mg for 8 weeks. Allopurinol was 100 mg once daily for 4 weeks and 100 mg twice daily for 12 weeks. Panel a: % change from baseline in sUA in study 1was analyzed by ANCOVA with baseline sUA and tophus status (absence/presence) during screening as covariates and treatment group as fixed effect. In study 2, % change from baseline in sUA was analyzed by ANCOVA with treatment group, gout (absence/presence) and type of hyperuricemia as fixed effects and baseline sUA as a covariate. Panel b: Proportion of patients with sUA <6.0 mg/dL or <5.0 mg/dL in study 1 was analyzed by Cochran-Mantel-Haenszel statistic stratified by tophus status (absence/presence) during screen and using nonresponder imputation. In study 2, proportion of patients with sUA ≤6.0 mg/dL was summarized by treatment group where missing data was imputed using nonresponder imputation. ANCOVA: analysis of variance; sUA: serum urate.

3.3. Safety

The duration of treatment for each patient ranged from 1 to 183 days in study 1 and from 12 to 173 days in study 2. TEAEs were reported for 61.0% to 65.9% of patients across the placebo and pooled verinurad groups in both studies (Table 3). The most frequently reported TEAE was upper respiratory infection in study 1 and nasopharyngitis in study 2. Both were reported by similar percentages of patients in the pooled verinurad and placebo groups and in the allopurinol group in study 2. TEAEs with a higher incidence in the pooled verinurad group than the placebo group in study 1 included nasopharyngitis (7.8% versus 2.4%), hypertension (5.4% versus 2.4%), arthralgia (4.7% versus 2.4%), and headache (4.7% versus 0); in study 2 they included back pain (5.7% versus 2.5%), diarrhea (3.3% versus 0%), and bronchitis, constipation, and increased blood creatinine (2.4% versus 0%, each).

Table 3. Summary of adverse events in study 1 and study 2.

	Study 1 (N = 171)		Study 2 (N = 204)
Adverse event category	Placebo (n = 42) n (%)	Verinurad pooled (n = 129) n (%)	Placebo (N = 40) n (%)	Verinurad pooled (n = 1 23) n (%)	ALLO (n = 41) n (%)
Any TEAE	27 (64.3)	85 (65.9)	24 (60.0)	75 (61.0)	23 (56.1)
Severe or life-threatening TEAEs	2 (4.8)	7 (5.4)	1 (2.5)	6 (4.9)	1 (2.4)
Any TEAE at least possibly related to randomized study medication	6 (14.3)	26 (20.2)	1 (2.5)	9 (7.3)	1 (2.4)
Any serious TEAE	1 (2.4)	5 (3.9)	1 (2.5)	2 (1.6)	1 (2.4)
Any fatal TEAE	0 (0.0)	0 (0.0)	0 (0)	1 (0.8)	1 (2.4)
Any TEAE leading to randomized study medication discontinuation	0 (0.0)	4 (3.1)	1 (2.5)	4 (3.3)	1 (2.4)
Any TEAE leading to study withdrawal	0 (0.0)	0 (0.0)	1 (2.5)	5 (4.1)	1 (2.4)

ALLO: allopurinol; TEAE: treatment emergent adverse event.

Serious AEs (SAEs) in study 1 were reported for one patient (2.4%) in the placebo group (pneumonia) and five patients (11.6%) in the verinurad group (colitis, wound infection, dyspnea, post-procedural hemorrhage, and transient ischemic attack). One patient in the verinurad group in study 2 experienced two SAEs (subarachnoid hemorrhage and VIIth nerve paralysis) during the follow-up period and died due to the subarachnoid hemorrhage described above. Another patient in the verinurad group had a silent myocardial infarction, while one patient in the placebo group had a hand fracture. No SAEs were considered as related to randomized study medication.

Four patients in study 1 discontinued randomized study medication due to nonserious TEAEs. All four patients were randomized to verinurad and discontinued due to TEAEs of sinus tachycardia, increased blood pressure, feeling jittery, nausea, and hot flash (all in one patient), and hyperbilirubinemia, increased blood creatinine, and ECG QT prolonged plus sinus tachycardia in one patient each. All were considered by the investigator to be possibly related to the randomized study medication. One additional patient in the verinurad group discontinued randomized study medication and withdrew from the study due to a pretreatment AE of hyperkalemia that started on day 1. In study 2, seven patients discontinued randomized study medication. One TEAE of dyspepsia in the placebo group, two of increased blood creatinine, and one of renal impairment in the verinurad group were considered related to the study medication; the other two events in the verinurad group were subarachnoid hemorrhage and myocardial infarction. One patient in the allopurinol group had a TEAE of bile duct stone.

As described in the Methods, all TEAE PTs mapping to the MedDRA Acute Renal Failure SMQ version 14.0 (Supplemental Material Table 1) were reviewed. Acute renal failure TEAEs were reported in study 1 for six patients in the pooled verinurad group (PT renal failure, three; PT increased blood creatinine, three) and one patient in the placebo group (increased blood creatinine) (Table 4). One patient in the verinurad group also had increased blood urea. None of the renal failure TEAEs were serious and there was no apparent relationship between occurrence of events and verinurad dose. In study 2, acute renal failure TEAEs were reported for four patients in the pooled verinurad group (PT increased blood creatinine, three; PT renal impairment, one). All were considered severe and related to study medication. Two patients with increased blood creatinine and the one with renal impairment discontinued the study treatment due to these events.

Table 4. Renal adverse events.

	Study 1 (N = 171)		Study 2 (N = 204)
	Verinurad pooled (n = 129)	Placebo (n = 42)	Verinurad pooled (n = 123)	Placebo (n = 40)	Allopurinol (n = 41)
Patients [n (%)] with sCr Above Baseline by Laboratory Testing^a
sCr ≥1.5x baseline	11 (8.5)	1 (2.4)	21 (17.1)	0	0
sCr ≥2.0x baseline	4 (3.1)	0	5 (4.1)	0	0
Patients [n (%)] with Events in the MedDRA SMQ: Acute Renal Failure^b
	6 (4.6)	1 (2.4)	4 (3.1)	0	0
Patients [n (%)] with Preferred Terms Mapping to the Acute Renal Failure MedDRA SMQ^b
Increased blood creatinine	3 (2.3)	1 (2.4)	3 (2.3)	0	0
Renal failure	3 (2.3)	0	0	0	0
Renal impairment	0	0	1 (0.8)	0	0

^aWhile listed as adverse events in the table, they were not all classified as adverse events by the investigators. Only abnormal laboratory values considered clinically significant by the investigator were reported as adverse events;

^bReported by the investigators. Full set of preferred terms related to “Acute Renal Failure” SMQ are available in Supplementary Table 1.

sCr: serum creatinine; SMQ: standard medical query.

3.4. Serum creatinine elevation

As described, laboratory abnormalities (e.g., serum creatinine elevations.) were only classified as TEAEs if they were considered by the investigator to be clinically significant. Eleven patients (8.5%) in the pooled verinurad group had 13 sCr elevations ≥1.5× baseline in study 1; one patient in the placebo group had an elevation (Table 4). Eight of the 13 elevations (61.5%) in the pooled verinurad group had resolved (sCr ≤1.2 × baseline) by the last study visit, seven (53.8%) without an interruption of study medication and one (7.7%) with an interruption. Five elevations (38.5%) had not resolved by the last study visit. The elevation in the placebo group had resolved by the last study visit following an interruption of study medication. Twenty-one patients (17.1%) in the pooled verinurad group in study 2 had 21 sCr elevations ≥1.5× baseline; no one in the allopurinol or placebo group had an elevation (Table 4). Twenty of the 21 elevations (95.2%) had resolved by the last study visit, 11 (52.4%) without interruption of study medication and 9 (42.9%) with an interruption. One elevation (4.8%) was unresolved by the end-of-study visit.

Only patients in the pooled verinurad group of either study had sCr elevations ≥2.0× baseline (study 1: 4 patients, 4 elevations; study 2: 5 patients, 5 elevations). Three of the four elevations (75.0%) in study 1 had resolved by the last study visit without an interruption of study medication; one had not resolved. All five events in study 2 had resolved but only after an interruption of study medication.

There were no clinically relevant findings for other laboratory investigations, vital signs, or ECGs in either study, with the exception of the ECG QT prolongation that led to discontinuation of study medication in study 1.

3.5. Gout flares

The percentage of patients in study 1 who experienced a gout flare was similar for the placebo (n = 18; 42.9%) and the pooled verinurad (n = 58; 45.0%) groups. Fewer patients in study 2 experienced a gout flare but the percentage was similar for the placebo (n = 4; 10.0%), allopurinol (n = 4; 9.8%), and the pooled verinurad (n = 13; 10.6%) groups.

3.6. Pharmacokinetics

A summary of verinurad plasma concentrations in study 1 and study 2 is shown in Table 5. Within each population, the increase in plasma verinurad concentration was generally dose dependent, while plasma verinurad concentrations in Japanese patients were higher than those in Western patients at the same dose levels.

Table 5. Summary of plasma verinurad concentrations from sparse samples collected in study 1 (week 12 and week 24) and study 2 (week 16 and week 24).

	Study 1						Study 2
Group	Group 1		Group 2		Group 3		Group 1		Group 2		Group 3
Week	WK12	WK24	WK12	WK24	WK12	WK24	WK16	WK24	WK16	WK24	WK16	WK24
Dose (mg)	5	5	10	10	12.5	12.5	5	7.5	10	12.5	12.5	15
N	36	39	39	37	40	39	38	35	39	37	41	39
Mean (ng/mL)	4.62	6.18	8.80	13.2	11.9	13.7	12.0	15.5	32.7	30.0	38.0	31.3
SD (ng/mL)	4.77	4.50	7.07	12.2	10.2	8.6	14.3	10.5	26.5	28.5	29.4	18.8
Median (ng/mL)	3.54	5.94	8.27	9.40	8.92	13.3	7.62	13.6	25.4	25.8	32.4	31.1
Range (ng/mL)	(0, 20.0)	(0, 15.1)	(0, 27.3)	(0, 49.1)	(0, 43.4)	(0, 37.4)	(0.739, 75.5)	(0, 39.0)	(10.8, 164)	(3.18, 170)	(0.170, 158)	(0, 71.5)

SD: standard deviation; WK: week.

4. Discussion

The current studies investigated the efficacy and safety of verinurad monotherapy at various daily doses for up to 24 weeks in either Western patients with gout or Japanese patients with gout or asymptomatic hyperuricemia. Verinurad reduced sUA levels in a dose-dependent manner in both patient populations at week 12 (up to 34% in study 1) or week 16 (up to 56% in study 2). Concurrent with the reductions in sUA, verinurad increased the percentage of patients who achieved sUA <6.0 mg/dL or <5.0 mg/dL at week 12 (up to 57% in study 1) or who achieved sUA ≤6.0 mg/dL at week 16 (up to 98% in study 2). The reductions in sUA and the percentages of patients who achieved the target sUA level were maintained to week 24 in both studies. In contrast, only 30% of patients given lesinurad 400 mg qd achieved sUA <6.0 mg/dL at month 6 [10]. Thus, verinurad is both more potent and more efficacious than lesinurad. In theory, the potency of verinurad, along with its PK properties, may enable it to be administered at a low dose, which could potentially lessen drug–drug interactions in patients with gout, many of whom are also being treated for hypertension, cardiovascular disease, diabetes, and obesity. This potency may also be needed in patients not meeting therapeutic goals with existing regimens. 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 [24–26].

Verinurad appears to be more potent and efficacious in Japanese patients with gout or asymptomatic hyperuricemia than in Western patients with gout. Greater percentage reductions in sUA and more patients achieving sUA <6.0 mg/dL were observed at week 16 in study 2 than were observed at week 12 in study 1. These differences can be attributed to the greater exposure to verinurad in the Japanese patients where mean plasma concentrations of verinurad were 2.6–3.7 times greater than in Western patients. The greater exposure to verinurad was unexpected as an earlier study demonstrated only small differences in plasma verinurad concentration between healthy adult Japanese and non-Asian subjects given the same verinurad dose [21]. The reason for the much greater differences in exposure in the current studies is not known, but may somehow be related to the presence of disease in these patients.

Renal-related TEAEs and sCr elevations ≥1.5 × baseline occurred almost exclusively in the pooled verinurad group in both studies. Due to its mechanism of action as a selective uric acid reabsorption inhibitor, verinurad increases the fractional excretion of uric acid which has the potential for microcrystallization of uric acid in the renal tubules. This could have led to transient sCr elevations and acute kidney injury as observed in these studies. Undissociated urinary uric acid levels ≥20 mg/dL have been associated with an increase in the rate of nephrolithiasis in patients with gout treated with benzbromarone [27]. While no kidney stones were observed in these studies, verinurad is not being pursed as monotherapy due to the potential risk of renal-related AEs; it is in development as combination therapy with an XOI.

It may be instructive to consider the similarities and differences between verinurad and benzbromarone, another URAT1 inhibitor. Benzbromarone is used as first-line treatment of hyperuricemia in Japanese patients with gout who under-excrete uric acid [7,8]. Its use is generally considered to not be associated with renal AEs, although no large well-controlled 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). The lower rate with benzbromarone likely allows it to be safely dosed as monotherapy. Benzbromarone also has prolonged urate-lowering activity because it has an active metabolite with a long half-life [28]. The long duration of action enables a steady urinary excretion of uric acid, which prevents the uric acid from precipitating. 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].

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 × baseline [24–26]. These results are consistent with those of lesinurad, which is associated with significant increases in renal AEs when given as monotherapy [10]. The rate of renal AEs decreased substantially when lesinurad was combined with an XOI [11–13].

Limitations to these studies include the short study duration, especially to assess the longer-term safety and efficacy of verinurad monotherapy. The up-titration of the study medication, particularly in study 2, made it difficult to identify a dose response for safety. Other limitations include the limited number of female patients and of patients with moderate renal impairment.

5. Conclusion

Verinurad resulted in sustained reductions in sUA in patients with gout or asymptomatic hyperuricemia in Japan and in patients with gout in the United States. Owing to the potential for renal-related AEs, verinurad is not recommended as monotherapy for the treatment of asymptomatic hyperuricemia or gout.

Conflict of interest

Jesse Hall, Zancong Shen, Sha Liu, and Scott Baumgartner are former employees of Ardea Biosciences, Inc., a member of the AstraZeneca group. Yasushi Ito was a consultant to Ardea Biosciences, Inc. David Fitz-Patrick, Kent Roberson, Kiyoshi Niwa, Takabumi Fujimura, and Koji Mori received study funding from Ardea Biosciences, Inc.

Acknowledgments

We thank the investigators for inclusion and care of patients during the study. Editorial support for this manuscript was provided by Tom Claus of PAREXEL, which was funded by AstraZeneca. The study sponsor had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and review and approval of the manuscript.

Additional information

Funding

This clinical study was funded by Ardea Biosciences, Inc., a member of the AstraZeneca group.