Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricaemia: a randomized controlled phase II study

Abstract

Introduction

Gout is one of the most common rheumatic diseases, caused by high serum uric acid (sUA) level, with a recently estimated prevalence of 1‒3% in Chinese adults [1]. Elevated sUA levels (hyperuricaemia) lead to the deposition of monosodium urate crystals within joint structures and soft tissues, resulting in episodes of acute inflammation in articular and periarticular structures [2].

For long-term gout management, the ACR recommends a target sUA level of ˂6 mg/dl while EULAR recommends ≤6 mg/dl in patients with gout and ˂5 mg/dl in patients with tophaceous gout [3, 4]. Xanthine oxidase inhibitors (XOIs) such as allopurinol and febuxostat, which block synthesis of uric acid, are widely used in clinical practice [3]. However, 30‒70% of patients receiving XOIs cannot achieve the target sUA level (˂6 mg/dl) [5]. In addition, the use of allopurinol is limited in Han Chinese patients due to its high risk of allopurinol hypersensitivity syndrome [6, 7]. Another option in the treatment of hyperuricaemia is uricosuric agent [2]. Benzbromarone and probenecid are two common drugs of this type. But benzbromarone was withdrawn in the USA and some European countries due to serious hepatotoxicity [8]. Probenecid is not a selective inhibitor of organic anion transporters and its potential for drug–drug interactions limits its clinical use [9]. Lesinurad, a novel uricosuric agent, which can selectively inhibit urate transporter 1 (URAT1), has been approved in the USA and the European Union. The drug is labelled as a combination therapy with an XOI to treat hyperuricaemia patients associated with gout who fail to achieve target sUA with XOI alone [10]. Lesinurad monotherapy, however, is not recommended due to the higher occurrence of elevated serum creatinine (sCr) concentration and renal-related adverse events [11]. Until now, there remains a great need for effective treatments with better safety profile for patients with hyperuricaemia.

SHR4640 is a highly selective inhibitor of URAT1, which is a major urate reabsorption transporter in kidney. It is known that blood uric acid is tightly regulated by its reabsorption and excretion in the kidney. After crossing through the glomerulus, ∼90% of uric acid is reabsorbed by proximal tubular URAT1. Therefore, inhibition of URAT1 could enhance urate excretion and thus decrease serum urate level. In our phase I study, SHR4640 showed a great potential for sUA lowering with a favourable safety profile. This multicentre, randomized, double-blind, controlled phase II clinical trial (FOCUS) was conducted to evaluate the efficacy and safety of SHR4640 in Chinese subjects with hyperuricaemia (with or without gout).

Methods

Subjects

Subjects aged 18−70 years with a BMI ≥18 kg/m² and ≤32 kg/m² who were diagnosed with hyperuricaemia were enrolled according to the Chinese multi-disciplinary consensus on the diagnosis and treatment of hyperuricaemia [12]. Eligible subjects had also to meet any of the following criteria: sUA levels ≥480 µmol/l with gout; sUA levels ≥480 μmol/l without gout but with comorbidities (hypertension, hyperlipidaemia or diabetes mellitus), or sUA levels ≥540 μmol/l without gout and complications.

Exclusion criteria included an estimated glomerular filtration rate (eGFR) ˂60 ml/min (as calculated via the Modification of Diet in Renal Disease); a history or presence of urolithiasis; and gout flares within 2 weeks before randomization. The complete inclusion and exclusion criteria are provided in Supplementary Table S1, available at Rheumatology online.

Trial design

Treatment procedures

FOCUS was a multicentre, randomized, double-blind, controlled phase II clinical trial conducted in China to evaluate the efficacy and safety of SHR4640 in Chinese hyperuricaemia subjects with or without gout (ClinicalTrials.gov identifier: NCT03185793). The study included an approximate 3-week screening period, a 5-week double-blind treatment period, and a 1-week safety follow-up period.

Eligible subjects were randomly (stratified by baseline renal function) assigned in a ratio of 1:1:1:1:1 to receive 2.5 mg/5 mg/10 mg of SHR4640, 50 mg of benzbromarone or placebo orally once daily in the morning before breakfast (Supplementary Fig. S1, available at Rheumatology online). Allocation was done via an interactive web-response system. The investigators at each site assigned subjects on the basis of the randomization sequences obtained from the system. All investigators, patients and the sponsor of the study were masked to treatment group. At least eight subjects with an eGFR ≥60 ml/min and ˂90 ml/min were required in each group. Subjects were required to drink at least 2 l water per day to remain hydrated, as recommended by ACR guidelines [3].

To prevent gout flares caused by dramatic decrease in uric acid level, SHR4640 was initiated at a dose of 1 mg for all SHR4640 groups at week 1, and the initial dose for benzbromarone was 25 mg. From the second week, SHR4640 and benzbromarone were added to the pre-set dose for an additional 4 weeks. Compliance with study medication was determined by medication dispensing records, verification of the returned medication packaging and any remaining medication at each study visit.

The study protocol was reviewed and approved by the independent ethics committee at each investigative site (Supplementary material). The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization/Good Clinical Practice, and Chinese laws and regulatory requirements. Each subject provided written informed consent before participation. The study was conducted between 20 July 2017 and 20 July 2018.

Evaluations

The primary end point was the proportion of subjects with sUA ≤360 µmol/l at week 5 in each treatment group. Secondary end points included the proportion of patients with sUA levels ≤360 µmol/l at week 1, 2, 3 and 4; the absolute and relative change in sUA level from baseline at each week; the proportion of subjects achieving sUA level ≤360 µmol/l constantly during week 3 to week 5; and the proportion of subjects with gout flares requiring treatment during the 5-week treatment.

Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory data, physical examination, vital signs and 12-lead electrocardiograms.

Statistical analysis

Efficacy was assessed in the full analysis set, which comprised all randomized subjects who received at least one dose of study medication, had baseline sUA assessment and at least one post-baseline efficacy assessment. Safety was analysed in all subjects who had at least one dose of study medication and one post-treatment safety assessment. Statistical analyses were performed using SAS (version 9.4; SAS Institute, Cary, NC, USA), and all statistical tests were two-sided with a significance level of 0.05.

Primary end point was analysed using the logistic regression analysis. For subjects who withdrew early from the study treatment or missed the sUA assessment, the last-observation-carry-forward (LOCF) method was used to impute week 5 sUA assessment. To obtain the overall false-positive rate, a modified sequence testing procedure was employed between SHR4640 groups and placebo in the order from SHR4640 higher dose to lower dose groups.

The absolute and relative change in sUA level from baseline at each week were analysed by a covariance (ANCOVA) model with baseline sUA and renal function during screening as covariates and treatment group as fixed effect. The comparison of frequency of gout flares between SHR4640 groups and placebo group was analysed using negative binomial regression. The incidence of gout flares requiring treatment during the 5-week treatment, the proportion of subjects achieving sUA ≤360 μmol/l at week 1, 2, 3, 4, and the proportion of subjects maintaining an sUA ≤360 μmol/l constantly during week 3−5 were analysed using logistic regression analysis. Subjects with missing data in the evaluation of proportion of subjects achieving sUA ≤360 μmol/l for three consecutive weeks from week 3 to week 5 were considered non-responders (non-completers as failure, NCF).

Approximately 200 subjects were planned to be recruited for an allocation of 40 to each treatment group. The sample size was calculated to provide 90% power to achieve a superiority between SHR4640 (10 mg) and the placebo group (28.1% difference) if the placebo group had a 1.9% response rate at week 5, using Fisher’s exact test with a two-sided α-level of 0.05 and a dropout rate of 10%.

Results

Distribution of the study subjects

Of the 362 subjects screened, 198 were randomized at 21 sites in China. Of these, 197 subjects received at least one dose of investigational study agent. Eight out of 197 subjects did not complete the study (Fig. 1).

Fig. 1

Distribution of the study subjects

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Demographic characteristics and clinical history

Demographics and baseline characteristics were similar among groups (Table 1). The subjects were predominantly male (99.5%), with a mean (s.d.) age of 42 (13) years and a mean (s.d.) BMI of 26.8 (2.88) kg/m². The mean (s.d.) The sUA level at baseline was 598.3 (94.01) µmol/l, and 95.9% of subjects had a history of gout flare. A total of 39.6% of subjects had an eGFR between 60 and 90 ml/min.

Compliance with study medications

All subjects in SHR4640 or placebo groups and 97.4% of subjects in benzbromarone group exhibited ≥80% compliance with study medications.

Efficacy assessments

Primary end point

The proportion of subjects who achieved sUA ≤360 µmol/l by week 5 was 32.5% in the 5 mg SHR4640 group, 72.5% in the 10 mg SHR4640 group and 61.5% in the benzbromarone group (Fig. 2), while no subject achieved the target sUA level after a 5-week treatment with 2.5 mg of SHR4640 or placebo. Significantly more subjects achieved sUA ≤360 µmol/l by week 5 in the 5 mg and 10 mg SHR4640 groups compared with the placebo group (P = 0.011 and P ˂ 0.001, respectively). The proportion of subjects achieving the target sUA level was numerically higher in the 10 mg SHR4640 group compared with the benzbromarone group (72.5% vs 61.5%). Results assessed using the observed case and NCF were consistent with the LOCF analysis (data not shown).

Fig. 2

Proportion of subjects that achieved a sUA ≤360 µmol/l at each weekly visit

*P < 0.05 vs placebo; †P < 0.01 vs placebo; ‡P < 0.001 vs placebo. sUA: serum uric acid.

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Secondary end points

The proportion of subjects who achieved sUA ≤360 µmol/l was higher in the 5 mg and 10 mg SHR4640 and benzbromarone groups compared with the placebo group at week 2, week 3 and week 4, respectively (P ˂ 0.01 for each comparison; Supplementary Table S2, available at Rheumatology online).

The absolute reduction in sUA levels from baseline at week 5 was greater in all SHR4640 groups than in the placebo group (P < 0.001 for each comparison) and displayed in a dose-dependent manner. The relative reduction in sUA at week 5 was 18.1%, 32.7%, 46.8% and 41.8% in the 2.5 mg, 5 mg and 10 mg SHR4640 and benzbromarone groups, respectively, compared with 5.9% with placebo (Fig. 3).

Fig. 3

Absolute and relative change from baseline in sUA levels at each weekly visit. (A) Mean absolute sUA change from baseline. (B) Mean relative sUA change from baseline. At week 1, SHR4640 and placebo were received at 1 mg dose and benzbromarone at 25 mg dose. Since week 2, SHR4640, placebo and benzbromarone were added to pre-set dose. Values are mean (s.d.). sUA: serum uric acid.

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The proportion of subjects whose sUA level was maintained at ≤360 µmol/l for three consecutive weeks from week 3 to week 5 reached 27.5% in the 5 mg SHR4640 group, 60.0% in the 10 mg SHR4640 group and 41.0% in the benzbromarone group. No subject in the 2.5 mg SHR4620 group or placebo group hit the target at any time point.

The proportion of subjects with gout flares requiring treatment during the trial was similar in all groups (42.5%, 45.0% and 42.5% in 2.5 mg, 5 mg and 10 mg SHR4640 groups, respectively, 41.0% in the benzbromarone group, and 39.5% in the placebo group).

Safety assessments

Adverse events

TEAEs were reported in 75.0%, 75.0%, 90.0%, 87.2% and 81.6% of subjects with 2.5 mg, 5 mg, 10 mg SHR4640, benzbromarone and placebo, respectively (Table 2). Most TEAEs were mild or moderate, and no serious TEAEs or death were observed. The most common TEAEs were gout flares (43.1%), upper respiratory tract infection (17.3%), diarrhoea (6.1%), hyperlipidaemia (6.1%), arthralgia (6.1%), increased blood creatinine (5.6%), increased alanine aminotransferase (5.1%) and increased blood triglycerides (5.1%) in total subjects (Supplementary Table S3, available at Rheumatology online). Incidences of treatment-related TEAEs were comparable across all groups (47.5%, 55.0%, 52.5%, 48.7% and 55.3% in subjects taking 2.5 mg, 5 mg, 10 mg SHR4640, benzbromarone and placebo, respectively). Five (2.5%) of 197 subjects discontinued study treatment due to TEAEs: one in the placebo group, one in the 5 mg SHR4640 group, one in the 10 mg SHR4640 group and two in the benzbromarone group.

Renal safety analyses

Renal-related TEAEs in each treatment group are listed in Supplementary Table S4, available at Rheumatology online. Among these treatment groups, the most frequently reported renal-related TEAEs was increased sCr (5.6%, n = 11), and this was reported in 7.5% (n = 3), 12.5% (n = 5) and 7.9% (n = 3) of subjects receiving 5 mg, 10 mg SHR4640 and placebo, respectively.

Elevation in sCr level ≥1.5 times (<2.0 times) baseline level occurred in 5.0% (n = 2) of subjects in the 10 mg SHR4640 group (NCI-CTCAE grade 2). Of these, one subject had an increase in sCr level from 95 μmol/l at baseline to 166 μmol/l, which decreased to 126 μmol/l with the intervention of study medication; the sCr level of another subject increased from 72 μmol/l at baseline to 124 μmol/l, and decreased to 87 μmol/l without intervention. Elevations in sCr in the other treatment groups were mild (NCI-CTCAE grade 1), and no subjects had sCr levels elevated ≥1.5 times baseline level. Post hoc analyses revealed that more subjects with eGFR ˂90 ml/min had sCr elevations compared with subjects with eGFR ≥90 ml/min (Supplementary Table S5, available at Rheumatology online).

Discussion

In the present phase II study, we investigated the efficacy and safety of SHR4640 (2.5, 5 and 10 mg) monotherapy in Chinese hyperuricaemia subjects with or without gout. Based on the ACR guidelines, we defined sUA ≤360 µmol/l as the target sUA level for hyperuricaemia control in this study. The study demonstrated that SHR4640 (5 and 10 mg) significantly increased the proportion of subjects achieving the target of good hyperuricaemia control at week 5 compared with placebo, with numerically more subjects treated with 10 mg of SHR4640 attaining such target than that of benzbromarone. SHR4640 also associated with a rapid onset of sUA reduction since a maximum clinical efficacy was observed 2 weeks after once daily administration of SHR4640 regardless of dosage. The extent of reduction in sUA levels was dose-dependent.

The incidences of gout flare requiring treatment were similar across all groups in the present study. It has been well documented that a rapid reduction in sUA after the initiation of urate-lowering therapy results in the remodelling of urate crystal deposits during its dissolution, and acute inflammation at the joints, which is the root cause for painful gout flare [13]. In the present study, we observed that the proportion of subjects with gout flares was higher than that in other clinical trials with sUA-lowering drugs [11, 14]. This may be explained by the fact that the gout flare prophylaxis was not applied in the present study.

The safety profile of SHR4640 was favourable. The majority of TEAEs were mild or moderate, without serious TEAEs or death. The incidences of TEAEs were comparable across treatment groups. In addition, the TEAEs in all SHR4640 treatment groups appeared not to be dose-related.

Renal dysfunction is considered to be a potential risk for uricosuric agents, because the increased excretion of uric acid may lead to microcrystallization of uric acid in the renal tubule, which will further cause epithelium injury [15]. The renal safety analyses in this study showed that the incidences of renal-related TEAEs were low in all groups. Subjects treated with 10 mg of SHR4640 had a slightly higher incidence of sCr elevation compared with the other groups. The elevation of sCr ≥1.5 times baseline occurred in two subjects taking SHR4640 10 mg, and notably, the elevation of sCr was transient and reversible, and one of them relieved without any intervention. In a phase III study with lesinurad in patients who had gout and were intolerant to XOIs, a total of 24.3% and 8.4% of patients had sCr elevation ≥1.5 times and ≥2.0 times baseline after a 6-month treatment, respectively [11]. Verinurad monotherapy elevated sCr ≥1.5 times and ≥2.0 times baseline level in 17.1% and 4.1% of Japanese patients with hyperuricaemia with or without gout after a 24-week treatment, respectively [14]. The proportions of subjects with sCr elevation ≥1.5 times and ≥2.0 times baseline were lower in this study compared with studies noted above, which might partly be attributed to the short study duration in our trial (5 weeks). Further studies evaluating the long-term activity and safety of SHR4640 are warranted.

The present study showed a tolerable safety profile with SHR4640 monotherapy in hyperuricaemia subjects with or without gout. Lesinurad must be taken in combination with an XOI, which provide decreased incidence of renal-related AEs compared with lesinurad monotherapy. In contrast, SHR4640 monotherapy showed promising efficacy, with a lower incidence of renal-related AEs, which represents a potential effective treatment option as first-line therapy in patients with hyperuricaemia with or without gout.

One limitation of the present study is the short duration of treatment, which makes it impossible to evaluate the long-term benefits in terms of sUA lowering, gout flare prevention, as well as complication reduction. Another limitation is the small sample size of subjects with asymptomatic hyperuricaemia (n = 8, 4.1% of all subjects), which limits the further efficacy and safety assessments for this subgroup. A further confirmatory clinical trial, which will evaluate the efficacy and safety of SHR4640 in the long-term, is under preparation.

Conclusion

Once daily 5 mg or 10 mg of SHR4640 showed a superior sUA-lowering effect with well tolerable safety profile after a 5-week treatment compared with placebo in Chinese subjects with hyperuricaemia with or without gout.

Acknowledgements

We thank the subjects and their families for their participation in this study, as well as the study teams at each of the study sites. We would also like to acknowledge Yanwen Wang (a medical writer at Jiangsu Hengrui Medicine) for medical writing support according to Good Publication Practice Guidelines.

Funding: This study was supported by Jiangsu Hengrui Medicine Co., Ltd.

Disclosure statement: R.N., Y.T. and T.Z. are employees of Jiangsu Hengrui Medicine Co., Ltd. The other authors declared no conflict of interests.

Data availability statement

The data underlying this article will be shared on reasonable request to the corresponding author.

Supplementary data

Supplementary data are available at Rheumatology online.

References

Author notes