Emerging uricosurics for gout

KEYWORDS:

• URAT1
• OAT4
• probenecid
• arhalofenate
• lesinurad
• benzbromarone
• PF-06743649

1. Introduction

Decreased renal uric acid excretion is the dominant abnormality driving increased uric acid burden and hyperuricemia in gout [1]. Since gout prevalence has increased, especially so in developed countries, in the last 2 decades [2], there is growing interest in novel, effective, and safe urate lowering therapy (ULT) options, including agents to potentially synergize with current ULT drugs [3]. Compared to the use of pharmacologic xanthine oxidase inhibition (XOI) to suppress uric acid generation, uricosurics have become far less frequently employed for uric acid lowering in gout in US medical practice [3]. This practice pattern likely reflects multiple factors, not simply complexities of 24-h urine uric acid determinations, and urolithiasis risk management measures such as increases in hydration and potential urine alkalinization [3].

Uricosuric monotherapy remains widely recommended as an acceptable alternative to the first-line XOI options for most cases of gout, and as a complementary measure to use of XOI inhibition, via allopurinol or febuxostat, for adherent patients refractory to appropriately dosed XOI drugs [3,4]. Notably, clinical development of uricosurics in gout has robustly increased in recent years [5]. This change aligns with major developments in understanding renal (and extrarenal) urate transport physiology [6–8], and genomic, pharmacogenomics, and precision medicine aspects of urate transport (exemplified by effects through the transporters URAT1, GLUT9, and ABCG2, encoded by SLC22A12, SLC2A9, ABCG2, respectively) [5,9–12]. In addition, clinical uricosuric development is timely, given the growing recognition that XOI therapy, by itself, not only decreases total renal uric acid elimination [8], but also fails to sufficiently lower serum urate to treatment target, and expeditiously improve clinical outcomes in gout in a substantial subset of adherent patients [3,4]. As such, there is new focus on readjustment of uric acid physiology via uricosuric addition onto established XOI therapy, aiming to optimize linked early and maintained outcome of serum urate at target, and the ultimate linked outcomes of tissue urate crystal deposit resolution and limiting recurrent acute flare frequency [3,4]. This editorial discusses emerging uricosuric agents and how they could be optimally used for gout.

2. Background

Gout is promoted by an increase in uric acid stores, typically reflected by hyperuricemia. Many factors, alone or in combination, can drive hyperuricemia in gout [7]. In health, ~ 90% of renally filtered urate is reabsorbed in the proximal tubule, with the remainder eliminated in the urine, and ~60–70% or the uric acid eliminated on a daily basis is renal. Decreased renal uric acid excretion is the most common and dominant cause of hyperuricemia in gout [6–8], where, the renal urate reabsorption system is substantially less saturated compared to non-gout, promoting greater uric acid retention [8]. Many patients with gout have chronic kidney disease, limiting daily glomerular filtration and elimination of circulating urate. Gout patients even more commonly have one or more significant comorbidities, medications, or other factors that impair renal uric acid excretion. Common examples include hypertension and manifestations of insulin resistance, thiazide or loop diuretics, and alcohol consumption, which increase renal urate reabsorption, by complex mechanisms [1]. Moreover, sugar consumption has surged in Western diets, and the capacity of chronic excess fructose consumption to promote reduced renal fractional excretion of uric acid, one of the mechanisms by which fructose promotes hyperuricemia, is modulated by certain SLC2A9 variants [13].

3. Available uricosurics for gout

Uricosuric therapy for gout predated allopurinol, with high-dose aspirin the first strategy used, but ultimately curtailed due to high risk of adverse events, as more recently the case for sulfinpyrazone in most clinical practices. Probenecid and lesinurad are US approved by the FDA directly for uricosuric activity in gout. Outside the USA, the potent uricosuric benzbromarone is widely available and frequently employed in many countries (e.g. in Southeast Asia).

The body of evidence for uricosuric medications in gout, prior to pivotal lesinurad studies, was limited by paucity of RCTs, many of short duration, none with a placebo arm, and with variable doses, relatively low subject numbers, and principally open-label designs, as recently systematically reviewed. In brief, despite lack of statistical power, the literature supports that benzbromarone and probenecid significantly lower uric acid, with magnitude of effects comparable to allopurinol, but with substantial adverse event profiles for both agents, including robustly increased risk of urolithiasis, and a small risk of severe hepatotoxicity with benzbromarone [14]. The hepatotoxicity risk accounts for the restricted availability of benzbromarone in many countries, and this author has not had personal experience with the drug. As such, this review focuses on other agents.

Lesinurad is the most extensively studied uricosuric in gout randomized clinical trials (RCTs), including phase II dose-finding comparison of lesinurad (200, 400, 600 mg/day) in combination with allopurinol vs. allopurinol and placebo [15], and large, phase III RCTs of lesinurad 200 mg or 400 mg/day in combination with allopurinol [16] or febuxostat (compared to XOI with placebo). The RCTs treated hyperuricemia refractory to XOI treatment, by definition a more challenging patient subset to achieve serum urate target [15,16]. More peer-review publications from these pivotal RCTS are awaited. However, evidence already presented in the public domain supports significant added efficacy, compared to XOI and placebo, of adding lesinurad onto either XOI drug, in achieving serum urate target (of <6 mg/dL with lesinurad and allopurinol [15,16]; and <5 mg/dL of lesinurad and febuxostat for gout with palpable tophi). Episodic AKI, occurring without gross urolithiasis, was significantly increased by lesinurad monotherapy, and at dosing above 200 mg/day in combination with XOI therapy [15,16]. The FDA approved lesinurad for gout in late 2015, at a dose of 200 mg/day, which increases serum urate target achievement via 10–20% serum urate lowering, when added to an XOI. Lesinurad is only approved for use in combination with an XOI, and with GFR >45 mL/min. By comparison, probenecid is not employed in stage 4–5 CKD, and probenecid (like benzbromarone and lesinurad), can be used in combination with an XOI [3,4,14].

Certain other drugs with uricosuric activity, but primarily intended for diseases other than gout, have substantial urate-lowering effects (i.e. >10% decrease in serum urate level), best exemplified by losartan and fenofibrate [3]. Most recently, the SGLT2 inhibitor canagliflozin, given for type 2 diabetes (T2D), decreased serum urate by ~13% (compared to placebo) in patients with T2DM, including those with baseline hyperuricemia.

4. The evolving role of uricosurics for gout and molecular pharmacology in the drug pipeline

Gout has large unmet need to improve oral ULT efficacy, and resolve urate crystal tissue deposits. This is particularly the case in the substantial subset of adherent patients truly failing appropriately dosed XOI monotherapy, but who are not clinically appropriate for costly treatment with uric acid-degrading pegloticase infusion therapy [3,4]. In clinical practice, off-label use of ‘non-primary’ uricosurics, particularly losartan and fenofibrate, can have useful adjunctive ULT effects in carefully selected patients with gout [3]. In this context, magnitude of serum urate-lowering effect can reach ~10% with losartan and somewhat more with fenofibrate, but clinical trials have been sparse [3]. The more potent uricosuric probenecid can be successfully added onto febuxostat ULT for truly XOI-refractory hyperuricemia and gouty arthritis, especially with non-resolving palpable tophi.¹ However, RCTS of combined probenecid and XOI therapy would be informative, since probenecid has substantial drug interactions and adverse event profiles that need attention in clinical practice [3,14].

Variants of SLC22A12, SLC2A9, and ABCG2 are associated with gout mediated by renal uric acid underexcretion [11]. Nevertheless, inhibition of the monocarboxylate-urate exchange transporter URAT1, the linchpin for renal urate reabsorption at the proximal renal tubule epithelial cell apical membrane, is the primary mechanism shared by most uricosurics, but with varying selectivity [12,17]. Significantly, a new generation of URAT1-inhibiting ULT drugs is in development [5], and includes agents with particularly potent, selective effects on URAT1 (e.g. verinurad (RDEA3170), currently in phase II), and a URAT1 inhibitory uricosuric with distinct anti-inflammatory properties that is associated with reduced frequency of acute gout flares, potentially by partial PPARγ agonism (i.e. arhalofenate, which has completed phase II) [18]. Significantly, PF-06743649, a dual XOI and uricosuric, had marked ULT efficacy (i.e. capacity to reach serum urate ~1–2 mg/dL), but development was stopped due to acute development of AKI in a few subjects [19].

5. Potential for precision medicine advances including improved uricosuric risk management

URAT1 inhibitor-binding sites have recently been mapped, with human URAT1 serine-35, phenylalanine-365, and isoleucine-481, in close proximity within the transport channel, mediating marked affinity increase for inhibitors [12]. Hence, future drug design efforts can more readily identify increasingly potent and selective oral uricosurics to combine with XOIs, to accelerate resolution of tissue urate crystal deposits by driving serum urate well below 4 mg/dL. However, the author’s opinion is that development efforts for highly potent uricosurics, even in combination use with an XOI that lessens total urinary uric acid excretion, need to be effectively coupled with risk management strategies for urolithiasis and other renal adverse events. Baseline measures to prevent urolithiasis include ample hydration, assessment for acid pH that increase uric acid and oxalate urolithiasis risk, potential urine alkalinization, and monitoring urine uric acid concentration for elevation at or above ~40 mg/dL (to screen for undissociated UA concentration >20 mg/dL) [3,20]. Further studies will be needed to test whether such measures can limit AKI (without gross urolithiasis), an adverse event in some treated with newer, potent primary uricosuric agents for gout [15,16,19]. Last, we need to better understand optimization of the clinical role, and safety and efficacy of potent primary uricosurics in stage 3 CKD.

6. Conclusions

Uricosurics, increasingly in clinical development, have a substantial role in ULT for gout, and can be particularly effective when added to baseline XOI treatment, for adherent patients who have not reached the target serum urate with appropriately dosed XOI monotherapy. Hydration, urine alkalinization, and monitoring renal uric acid excretion remain standard options to attempt to limit uricosuric adverse events including urolithiasis, but we do not yet understand if these measures can limit renal function impairment that occurs independently of gross urolithiasis. Advances in precision medicine could further help in improving patient selection for specific agent, and dosing, and improved risk:benefit ratios for uricosurics in gout.

Declaration of interest

R Terkeltaub has served as a consultant for ARDEA/Astra-Zeneca, CymaBay, SOBI, Revive, Selecta, Aequus Biopharma, ProteoThera, Horizon Pharma, and Relburn. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.

Notes

1. Author. Unpublished observations.