Novel uricosurics RHEUMATOLOGY. Thomas Bardin 1,2 and Pascal Richette 1,2. Abstract. Introduction REVIEW

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1 RHEUMATOLOGY Rheumatology 2018;57:i42 i46 doi: /rheumatology/kex433 Novel uricosurics Thomas Bardin 1,2 and Pascal Richette 1,2 REVIEW Abstract Objective. According to recent guidelines, the mainstay of urate-lowering therapies remains xanthine oxidase inhibition. However, some patients with gout show failure to achieve the predefined target of 5 6 mg/dl with xanthine oxidase inhibitors alone, so alternative drugs are needed. The aim of this study was to review studies of novel drugs targeting uric acid transporter 1 (URAT1) and/or other urate transporters for the management of gout. Methods. MeSH terms were used to identify phase 2/3 trials assessing the efficacy of novel uricosurics. A narrative review of novel drugs targeting URAT1 and/or other urate transporters for the management of gout is provided. Results. Lesinurad is a recently approved uricosuric that inhibits URAT1 and the organic ion transporter organic anion transporter 4 (OAT4). Phase 3 trials showed that lesinurad, combined with allopurinol or febuxostat, is a potent urate-lowering therapeutic with an acceptable safety profile. Arhalofenate, another emerging uricosuric, also interacts with URAT1 and organic anion transporter 4. Phase 2 trials suggested that it can both lower serum UA levels and reduce the risk of flares. Conclusions. New drugs inhibiting URAT1 should cover the unmet need for patients with failure to respond or with contraindications to xanthine oxidase inhibitors. Key words: uricosuric, urate-lowering therapy, lesinurad, arhalofenate, URAT1 Rheumatology key messages. Uricosurics are conceptually attractive drugs to lower urate levels.. Lesinurad, in combination with a xanthine oxidase inhibitor, is a potent urate-lowering drug.. Arhalofenate could prevent flares as well as reduce urate levels. Introduction Renal mechanisms are responsible for hyperuricaemia in 90% of patients with gout since impaired renal excretion is the main mechanism explaining the increase in the urate pool. Approximately 90% of the daily load of urate filtered by the kidneys is reabsorbed through the sequential activities of various transporters located in the renal proximal tubule and move uric acid across the apical and basolateral membranes [1]. These specific urate transporters are uric acid transporter 1 (URAT1), glucose transporter 9 and 1 Université Paris 7, UFR médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Service de Rhumatologie and 2 INSERM UMR-1132, Hôpital Lariboisière, and Université Paris Diderot, Sorbonne Paris Cité, Paris, France Submitted 12 June 2017; revised version accepted 12 October 2017 Correspondence to: Pascal Richette, Fédération de Rhumatologie, Hôpital Lariboisière, 2 Rue Ambroise Paré, Paris cedex 10, France. pascal.richette@aphp.fr organic anion transporter 1, 3 and 4 (OAT1, OAT3, OAT4) [2 4]. They are the target of old and new uricosurics (Fig. 1) and are therefore of great interest because they open new therapeutic perspectives for a disease whose prevalence is increasing in developed countries [5]. According to the EULAR [6] and ACR [7] recommendations for treating hyperuricaemia, uricosurics are recommended for patients with failure to respond or with contraindications to xanthine oxidase inhibitors (XOIs). Failure to respond to allopurinol is common because of the high prevalence of chronic kidney disease in patients with gout [8]. Indeed, in this case, and according to the EULAR but not the ACR, the dosage of allopurinol should be adjusted to creatinine clearance and often fails to achieve the predefined target. For these patients, uricosurics alone or in combination, depending on the drug, with an XOI is a therapeutic alternative [6]. Benzbromarone and probenicid act predominantly on URAT1 to prevent reuptake of uric acid (UA) at the proximal renal tubule and thus increase renal excretion of UA.! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Novel uricosurics FIG. 1Urate transporters at the proximal renal tubule OAT: organic anion transporter; URAT: uric acid transporter; ABCG2: adenosine triphosphate-binding cassette sub-family G member 2; GLUT: glucose transporter; UA: uric acid. Although effective in lowering serum UA (sua) levels as monotherapy, their use is limited by a lack of availability in most countries [9 11]. Furthermore, probenecid is not recommended for patients with severe renal impairment (estimated glomerular filtration rate <30 ml/min/1.73 m 2 ) because it is less effective [12], and the tolerance of benzbromarone, particularly liver toxicity, is a concern, mainly reported in Asia, as its occurrence in Europe seems rare [13]. Therefore, there is growing interest in novel uricosurics to cover the unmet need for treating hyperuricaemia. In this article we present a narrative review about novel uricosurics that have completed or are currently in phase 2/3 development. Methods In order to identify phase 2/3 trials assessing the efficacy of novel uricosurics for gout, we searched PubMed from January 2000 to May 2017 using the following terms: gout, hyperuricaemia, uricosurics, URAT, OAT, randomized trials, lesinurad, arhalofenate, urate-lowering therapy. Lesinurad In 2008, a reverse transcription inhibitor aimed at AIDS management was shown to have a substantial uricosuric effect by inhibiting URAT1 by means of one of its metabolites [14]. This metabolite was then developed for gout and named lesinurad. In addition to URAT1, lesinurad inhibits OAT4, another UA transporter in the kidney involved in diuretic-induced hyperuricaemia. In contrast, lesinurad does not interact with OAT1 and OAT3, responsible for drug drug interactions, which is an undesirable property of probenecid [15, 16]. Indeed, several classes of drugs interact with human OAT1 3, such as penicillin and MTX, whose concentrations can be increased when combined with probenecid [17]. Pharmacokinetics and pharmacodynamics Lesinurad absorption from the gastrointestinal tract is rapid, with a median time to maximum concentration (T max ) of h. The estimated elimination half-life (T ½ ) ranges from 2.7 to 1.5 h and is increased when the drug is taken with food. The urinary excretion of unchanged lesinurad accounts for 30 40% of the given dose. The sua-lowering effect is dose dependent. Lesinurad increases uricosuria over 6 12 h with a single 200 mg intake [18]. Two phase 1 studies showed lesinurad exposure increased with decreasing renal function and that the effects on sua level of a single lesinurad dose were similar with mild renal impairment and normal function, were reduced with moderate impairment and were greatly diminished with severe impairment [19]. Lesinurad is a moderate inducer of the CYP3A cytochrome and may lead to decreased exposure of drugs metabolized by this cytochrome, such as sildenafil, amlodipine or statins [20]. Lesinurad 400 mg has been shown to modestly decrease exposure to colchicine (by <25%) and indomethacin (35%) and not alter the pharmacokinetics of naproxen [21]. Lesinurad monotherapy Lesinurad was given at a daily dose of 400 mg/day as a monotherapy in the LIGHT study, a phase 2 trial. This was i43

3 Thomas Bardin and Pascal Richette a 6-month randomized double-blind study comparing lesinurad 400 mg/day to placebo in 214 gouty patients with sua levels >6.5 mg/dl [mean sua level 9.33 mg/dl (S.D. 1.51)] and contraindications or intolerance to XOIs. Exclusion criteria included a history of kidney stones and an estimated creatinine clearance <30 ml/min (Cockcroft Gault formula). The primary endpoint (sua level <6 mg/dl at month 6) was met by 29.9% of lesinurad-treated patients vs 1.9% in the placebo group (P < ). However, lesinurad-treated patients had more adverse events (AEs) than those taking placebo; in particular, none of the placebo-treated patients and 19.8% of those receiving lesinurad 400 mg/day experienced renal AEs, which led to a contraindication for lesinurad prescription as monotherapy [22]. Lesinurad allopurinol combination phase 2 trial Lesinurad was developed in combination with an XOI, a therapy recommended as a second or third line by the EULAR and ACR [6, 7]. The use of allopurinol or febuxostat combined with a uricosuric decreases the concentration of UA in urine and thus the risk of UA stones. In this regard, patients with a history of kidney stones were not excluded from the phase 2 [23] and phase 3 [24 26] placebo-controlled randomized trials exploring the outcomes of lesinurad associated with an XOI. A phase 2 study included 208 patients with sua levels >6 mg/dl who were receiving allopurinol ( mg/ day). Patients were randomized for 4 weeks into four groups: allopurinol + placebo or + lesinurad 200, 400 or 600 mg/day. Patients receiving lesinurad showed a dose-dependent reduction of sua level from baseline (16, 22 and 30% for lesinurad 200, 400 and 600 mg/day, respectively), with a mean 3% increase observed with placebo (P < , all doses vs placebo). The proportion of patients with a 1.5-fold increase in creatinine level was 0, 12.7 and 19.7% with lesinurad 200, 400 and 600 mg, respectively [23]. Lesinurad combined with an XOI in phase 3 trials The lesinurad development program has included three phase 3 trials combining lesinurad with allopurinol for two of them and with febuxostat for the third. The CLEAR 1 and CLEAR 2 replicate trials tested, over 1 year, the addition of lesinurad 200 or 400 mg or placebo to allopurinol in a total of 1220 patients who were required to be on stable allopurinol doses 5300 mg (5200 mg for moderate renal impairment) and have an sua level 56.5 mg/dl at screening and a history of two or more gout flares in the past 12 months. The primary endpoint was the proportion of participants meeting the sua target of <6.0 mg/dl by 6 months. Lesinurad (200 or 400 mg) with allopurinol achieved the sua target at 6 months by 2- to 2.5-fold that with allopurinol alone. None of the two doses were superior to placebo for the two key secondary endpoints (flare rate from months 6 to 12 after the end of flare prophylaxis and a tophus size decrease at 1 year), but the number of flares was very low and only a few included patients had clinical tophi at baseline [24, 25]. The CRYSTAL trial evaluated lesinurad 200 and 400 mg/ day combined with febuxostat 80 mg/day vs febuxostat monotherapy over 1 year in 330 patients with tophaceous gout. Inclusion criteria were uricaemia >8 mg/dl and not receiving a hypouricaemic drug or >6 mg/dl when taking febuxostat or allopurinol at a medically appropriate dose. Patients received febuxostat 80 mg/day before randomization, which led to a high proportion of patients receiving febuxostat alone who met the uricaemia target of <5 mg/l (46.8% at 6 months). The primary endpoint was the proportion of patients with a uricaemia target <5 mg/dl at 6 months. Only the results for the febuxostat lesinurad 400 but not 200 mg/day dosage reached statistical significance vs placebo for this primary endpoint. Notably, the primary endpoint was met by the low dose of lesinurad (200 mg/day) at all other time points of the 1 year trial, and the sua target of <5 mg/dl at 6 months was met with lesinurad 200 mg/day plus febuxostat in the CRYSTAL subgroup with uncontrolled hyperuricaemia at baseline, despite having received febuxostat pre-randomization. The rate of flares after the end of prophylaxis (6 12 months) did not differ between groups. At 1 year, both lesinurad doses achieved greater tophus area resolution vs placebo [26]. Both the CLEAR and CRYSTAL core trials were followed by a 1 year extension study in which patients receiving placebo were randomized to receive lesinurad 200 or 400 mg/day. Uricaemia reduction was maintained and tophus size and flare rate regularly decreased. Safety data were pooled from the three phase 3 trials, including 1500 gouty patients [27]. Overall, the incidence of treatment-emergent AEs (TEAEs) was similar across the three groups (lesinurad 200 or 400 mg/day, placebo). Most TEAEs were benign. In the core studies, TEAEs led to study withdrawal for 3.5, 3.9 and 5.3% of patients receiving placebo and lesinurad 200 and 400 mg/day, respectively. Serious TEAEs were reported in 5.6, 4.7 and 8.6% and lethal TEAEs in 0, 0.4 and 0.6% of the patient groups, respectively. In the core and extension pooled data, the incidence of serious TEAEs was 6.8 and 9.2/ 100 patient-years in the lesinurad 200 and 400 mg/day groups, respectively; the incidence of lethal TEAEs was 0.8/100 patient-years for both groups. A cardiovascular endpoint adjudication committee was appointed to the studies; the committee estimated the incidence of major adverse cardiovascular events at 0.71, 0.96 and 1.94/100 patient-years in the placebo and lesinurad 200 and 400 mg/day groups, respectively. These major adverse cardiovascular events consisted of cardiovascular deaths (0, 0.48 and 0.48/100 patient-years, respectively), non-fatal myocardial infarction (0.24, 0.48 and 1.70) and non-fatal stroke (0.71, 0 and 0). Therefore the cardiovascular risk in association with exposure to lesinurad has to be investigated, primarily in patients with a history of cardiovascular diseases. As for all uricosuric drugs, the renal safety of lesinurad deserves attention. Combined with an XOI, lesinurad did not increase the number of UA stones. However, even i44

4 Novel uricosurics though the mean serum creatinine levels did not change statistically during the phase 3 trials, a small number of patients experienced increased serum creatinine levels, particularly with 400 mg/day lesinurad. Overall, 2.3, 5.7 and 14.3% of patients receiving placebo or lesinurad 200 or 400 mg/day, respectively, showed an increased serum creatinine level 51.5-fold the baseline level; the proportions with 52-fold the baseline level were 0, 1.8 and 6.7%, respectively, and with 53-fold the baseline level were 0, 0.8 and 2.4%, respectively. Extension studies showed that these rare events also occurred in patients with long-term lesinurad treatment. Most of these increases in serum creatinine level were transient and resolved without interruption of lesinurad. Real side effects resulted in treatment discontinuation for 1.2, 3.3 and 1% of patients receiving lesinurad 200 or 400 mg/day and placebo, respectively [27]. Approval of lesinurad 200 mg Overall, the data produced in the lesinurad dossier led the European Medicines Agency to contraindicate the use of lesinurad as monotherapy and to approve its use at a daily dose of 200 mg in combination with an XOI in gout patients who did not achieve target sua levels with an adequate dose of an XOI alone. The 200 mg tablet should be co-administered at the same time as the morning dose of the XOI, with a recommended minimum allopurinol dose of 300 mg, or 200 mg for patients with moderate renal impairment; patients should be advised to stay well hydrated (e.g. 2 l of liquid/day). Contraindications include tumour lysis syndrome or Lesh Nyhan syndrome and a serum creatinine level <30 ml/min or kidney transplant. Renal function should be evaluated before lesinurad initiation and monitored periodically thereafter (e.g. four times per year). Patients with a serum creatinine level >1.5 times the pre-treatment value should be closely monitored and lesinurad should be stopped if the level increases more than two times the pre-treatment value or exceeds 4.0 ml/dl. Lesinurad is not recommended for patients with unstable angina, New York Heart Association class III or IV heart failure, uncontrolled hypertension or recent myocardial infarction. Other uricosurics in development By interacting with URAT1 and OAT4, arhalofenate inhibits the tubular reabsorption of UA and lowers the sua level. In addition, it has anti-inflammatory properties and can decrease the urate crystal stimulated release of IL-1b by modulating the peroxisome proliferator-activated receptor gamma pathway [10]. A phase 2b study assessed the potential for arhalofenate to decrease the risk of flares after ULT. In this double-blind 12-week study, 239 patients with three or more gout flares during the previous year and a baseline sua level of mg/dl who were not taking colchicine or ULT were randomized to receive arhalofenate once daily at 600 or 800 mg, allopurinol 300 mg, allopurinol 600 mg plus colchicine 0.6 mg or placebo. The primary outcome was flare incidence. The incidence was significantly lower with 800 mg arhalofenate than allopurinol alone (0.66 vs 1.24; P = 0.005) and placebo (1.13; P = ) and similar to that with allopurinol plus colchicine (0.40; P = 0.091). Given as monotherapy, arhalofenate is a weak uricosuric: the mean change in sua level was 12.5 and 16.5% with 600 and 800 mg arhalofenate, respectively, but was 28.8% with 300 mg allopurinol. This modest sua level reduction implies that this drug should be used in combination with an XOI. There was no safety signal in this trial [28]. Another phase 2 randomized study evaluated the sualowering effect of arhalofenate combined with febuxostat. In this open trial, one group received 600 mg/day arhalofenate for 2 weeks followed by a sequential weekly co-administration of febuxostat 80 and 40 mg/day, with 2 final weeks of febuxostat 40 mg/day as monotherapy. A second group received arhalofenate 800 mg/day for 2 weeks, then a weekly combination with febuxostat 40 mg/day and subsequently 80 mg/day and a final febuxostat 80 mg/day phase as monotherapy. The largest decrease in sua levels was seen at week 4 with arhalofenate 800 mg + febuxostat 80 mg, with absolute and relative changes from baseline of 5.8 mg/dl and 63%, respectively. No patients experienced any significant elevation in creatinine level. Arhalofenate is currently in phase 3 clinical development for use in fixed-dose combination with febuxostat as a once-daily oral gout treatment. Other uricosurics currently in development include verinurad [10], tranilast [29] and UR1102 [30]. Conclusions When available, novel uricosurics such as lesinurad should play an important role in the management of gout, because for some patients XOI alone does not give proper control. Because gout is caused by impaired renal excretion of UA in most affected cases, uricosurics that inhibit urate transporters and thus increase urinary uric acid excretion are conceptually attractive. A better knowledge of the renal tolerance of these new uricosurics is required and the risk:benefit ratios for uricosurics have yet to be determined. Supplement: This supplement was funded by Grunenthal. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: P.R. received fees for consultancy work or talks from AstraZeneca, Grunenthal, Ipsen, Menarini and Savient. T.B. received research grants from AstraZeneca, Ipsen and Menarini and fees for consultancy work or talks from Astella, AstraZeneca, Biomex, Grunenthal, Ipsen, Menarini, Novartis, Savient and Sobi. References 1 TanPK,FarrarJE,GaucherEA,MinerJN.Coevolutionof URAT1 and uricase during primate evolution: implications for i45

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