Emerging Therapies for Gout




Over the past decade much has been learned about the mechanisms of crystal-induced inflammation and renal excretion of uric acid, which has led to more specific targeting of gout therapies and a more potent approach to future management of gout. This article outlines agents being developed for more aggressive lowering of urate and more specific anti-inflammatory activity. The emerging urate-lowering therapies include lesinurad, arhalofenate, ulodesine, and levotofisopam. Novel gout-specific anti-inflammatories include the interleukin-1β inhibitors anakinra, canakinumab, and rilonacept, the melanocortins, and caspase inhibitors. The historic shortcomings of current gout treatment may, in part, be overcome by these novel approaches.


Key points








  • The most commonly used dose of allopurinol achieves urate reduction to the minimal target of less than 6.0 mg/dL in only 35% to 40% of gouty patients.



  • The new generation of uricosuric agents, when used in combination with current xanthine oxidase inhibitors, results in synergistic urate lowering not achievable by oral monotherapy.



  • Activation of the NLRP3-inflammasome and its promotion of interleukin-1β production are central to the pain and inflammation of gout. Interrupting this pathway is an effective way of treating gout-driven pain.



  • Corticotropin and other melanocortin peptides are effective in treating gout inflammation by interacting with the melanocortin receptors on macrophages.




The prevalence of gout worldwide has been steadily increasing over the past several decades. It has been estimated that in the United States 8.3 million people, or almost 3% of the population, suffer from gout, and 12% to 15% have hyperuricemia. Similar statistics are found in most developed countries. This expanding market would be enough to draw the interest of the pharmaceutical industry, but other factors have come into play. Over the past 10 years clinicians have been inundated with studies showing how inadequate the traditional approaches to this destructive arthritis have been. The time-honored therapies for treating the pain and inflammation of gout include nonsteroidal anti-inflammatories (NSAIDs), colchicine, and oral corticosteroids. Yet in the few controlled trials conducted with these agents, one finds that patients can expect to still have 50% of their acute pain after 36 to 48 hours of treatment regardless of which agent is used. Given the severity of acute gout symptoms, 50% reduction still leaves patients in considerable pain. Patients, physicians, and the pharmaceutical industry recognize a large unmet need for better and more specific anti-inflammatory approaches to gout.


Similarly, deficiencies in the use and efficacy of urate-lowering therapies (ULTs) have also been brought to light by recent studies. Allopurinol and probenicid had been the mainstays of gout therapy since the 1960s. Intolerance to these drugs usually meant that the gout patient would go untreated, and over years would slowly advance to a chronic crippling form of arthritis. The concept of treating the serum urate level (sUA) to a target was not widely held by the medical profession until this approach was strongly endorsed by the European League Against Rheumatism, and more recently in the American College of Rheumatology (ACR) guidelines on managing gout. Data from the early febuxostat trials by Takeda Pharmaceuticals demonstrated the inadequacy of the most commonly used dose of allopurinol (300 mg/d) in bringing patients’ sUA levels down to the target of less than 6.0 mg/dL, with only 35% to 40%, achieving even this minimal target. Again, the need for more aggressive treatment, as well as safer and more effective alternatives to allopurinol, was made apparent by study after study.


This article strives to outline the current therapies under development for the management of gout. In general, these agents build on a wealth of new information about the mechanism of gouty inflammation and urate elimination that was unknown a decade ago.




Urate-lowering therapies


Reducing sUA levels to below the solubility limit of urate in body fluids (ie, <6.8 mg/dL) has long been recognized as the definitive treatment for gout. The generally agreed therapeutic target of less than 6.0 mg/dL is safely below the solubility threshold, and will certainly prevent new crystallization of urate and further expansion of the body’s urate burden. Many studies support the concept that decreasing the sUA level to less than 6.0 mg/dL will, over time, reduce gout symptoms, shrink tophaceous deposits, and improve the quality of life. It has also been demonstrated that these good outcomes can be achieved more rapidly if the sUA level is pushed even lower than the minimal target of less than 6.0 mg/dL.


Allopurinol was approved by the Food and Drug Administration (FDA) in 1966, and clinicians have a lot of experience with its efficacy and toxicity profiles, although this is only true for daily doses of 300 mg or less. Although it is approved in doses of up to 800 mg/d, little is known about the safety of allopurinol in the higher dose ranges. Two new ULTs were introduced in the past 5 years. The new xanthine oxidase inhibitor, febuxostat, was approved in 2009 as an alternative for patients intolerant to allopurinol or for those who could not be adequately dosed with allopurinol because of chronic kidney disease. Febuxostat has a simpler dose escalation schedule than allopurinol, and was recommended in the recent ACR gout management guidelines as a first-line agent to accompany allopurinol.


Savient’s pegylated uricase, pegloticase, was approved by the FDA in 2010 for use in patients with severe, recalcitrant gout. It is the first parenteral therapy for gout, and has shown dramatic ability to lower serum urate and promote tophus resorption in subjects with advanced disease.


ULTs currently in development include lesinurad, arhalofenate, ulodesine, and levotofisopam.


Lesinurad (RDEA594)


Lesinurad is a uricosuric agent in development for the chronic management of gout and hyperuricemia. It was discovered by Ardea Biosciences as a major metabolite of a candidate nonnucleoside reverse transcriptase inhibitor, RDEA809, and was found to be the compound responsible for the urate-lowering effect observed in their study subjects. Lesinurad has been demonstrated to inhibit both the URAT-1 and OAT4 transporters in the renal tubule ( Fig. 1 ).




Fig. 1


Renal transport of urate in proximal tubule of kidney. Serum urate reaches the tubule lumen by glomerular filtration and by secretion through the proximal tubular epithelium. Secretion of urate is facilitated in the luminal direction by MRP4, UAT, ABCG2, and NTP1, and at the basolateral membrane by OAT1 and OAT3. Reabsorption of urate from the tubular lumen is facilitated by URAT1, OAT4, OAT10, and the short isoform of GLUT9, and at the basolateral membrane by the long isoform of GLUT9. ABCG2, adenosine triphosphate–binding cassette transporter; GLUT, glucose transporter; MRP, multidrug resistance–related protein; NTP, sodium phosphate transport protein; OAT, organic acid transporters; URAT, uric acid.

( Adapted from Basseville A, Bates SE. Gout, genetics and ABC transporters. F1000 Biol Rep 2011;3:23.)


Two phase 2b trials were conducted on gout patients including subjects with mild and moderate renal impairment. Study 202 enrolled patients with sUA of at least 8.0 mg/dL while not on other urate-lowering therapy. Study 203 enrolled patients with sUA of at least 6.0 mg/dL despite 10 weeks on a stable dose of allopurinol before starting lesinurad. Increased renal excretion of uric acid was demonstrated for lesinurad doses of 200, 400 and 600 mg daily, with no attributable serious adverse events. Gout patients with mild to moderate renal impairment in these two Phase 2b trials derived sUA lowering to an extent similar to that for patients with normal renal function.


Another multicenter open-label trial (RDEA599-111) investigated the efficacy and safety of lesinurad in combination with febuxostat. All subjects received either 40 or 80 mg febuxostat daily for 7 days followed by combination treatment with lesinurad, 400 mg daily for 7 days ( Fig. 2 ), then combination treatment with lesinurad 600 mg daily for 7 days (data not shown). The combination of lesinurad and febuxostat produced substantial additive urate lowering, with nearly 100% of subjects achieving sUA targets of less than 6.0 mg/dL, less than 5.0 mg/dL, and less than 4.0 mg/dL. This study demonstrated that combining drugs with complementary mechanisms of action produced significantly greater reductions in sUA than increasing the dose of a single agent.




Fig. 2


Lesinurad in combination with febuxostat shows additive urate-lowering effects in gouty subjects. RDEA594-11 multicenter, open-label study (n = 12) of febuxostat, 40 mg/d alone or in combination with 400 mg/d or 600 mg/d lesinurad. Target serum urate levels of less than 6 mg/dL to less than 2 mg/dL are shown. Measurements are made 12 hours after dose.


Ulodesine (BCX4208)


Ulodesine is an oral once-daily novel purine nucleoside phosphorylase (PNP) inhibitor being developed by BioCryst Pharmaceuticals for the chronic management of gout. Ulodesine blocks production of uric acid at the step higher in the purine catabolic pathway than xanthine oxidase inhibition ( Fig. 3 ).




Fig. 3


Terminal pathway of purine catabolism in humans. The breakdown of purine nucleosides and bases is regulated by 2 enzymes. Purine nucleoside phosphorylase allows the catabolism of the nucleosides, inosine and guanosine, to their respective purine bases, hypoxanthine and guanine. Hypoxanthine is converted to xanthine by xanthine oxidase while guanine is decimated to xanthine by guanase. Xanthine is further reduced to uric acid by xanthine oxidase.


A phase 2 placebo-controlled, dose-ranging trial of the efficacy and safety of ulodesine monotherapy involved 24 gout subjects in the placebo group and 85 gouty subjects divided into 5 ulodesine dosing arms ranging from 40 to 240 mg daily. The serum urate targets of less than 6.0, less than 5.0, and less than 4.0 mg/dL were achieved by 30%, 21%, and 0% of the 80 mg/d ulodesine group, respectively, and by 77%, 54%, and 23% of the 240 mg/d ulodesine group. Adverse events for all doses of ulodesine were not significantly different from those for placebo, but the higher doses did result in more diarrhea (20%) and rash (13%). Despite dose-related decreases in CD4 + , CD8 + , and CD20 + lymphocytes, there was no observed increase in infection. This finding was a theoretical concern because the inborn error in purine metabolism resulting from PNP deficiency is associated with a combined immunodeficiency.


A separate phase 2 trial tested the urate-lowering effects of combining low-dose ulodesine (20, 40, and 80 mg/d) with various doses of allopurinol ( Fig. 4 , data for 80 mg ulodesine not shown). Synergistic reduction in serum urate was observed with the ulodesine and allopurinol combination, with 100% of subjects taking 40 mg/d ulodesine and 300 mg/d allopurinol achieving the target sUA of less than 6.0 mg/dL.




Fig. 4


Ulodesine synergistically lowers serum urate when combined with allopurinol in gouty subjects. Percentage of patients achieving the target sUA level of less than 6.0 mg/dL is shown for ulodesine and allopurinol dosing groups.

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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Emerging Therapies for Gout
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