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143ISSN 1758-427210.2217/IJR.11.79 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(2), 143154

Drug Evaluation

Pegloticase: a new biologic for treating advanced gout

Among the rheumatic diseases, few are as well understood as gout. The cause of gout, prolonged hyperuricemia resulting from excess production or decreased excretion of uric acid (UA), was first described by Garrod in the mid-19th century [1]. Garrod also described a semiquantitative method for measuring UA crystals in serum, commonly called the thread test, and wisely postulated that urate deposition was the cause of gouty inflam-mation. The presence of UA in renal stones and monosodium urate in tophi was documented well before that by Woolaston in 1797 [1]. Even the genetic basis of our species susceptibility to hyperuricemia, the lack of a functional uricase gene, has been understood for decades.

The medical management of gout also has a long history. Hippocrates wrote that he habitually employed purgatives in the parox-ysms of gout. The control of joint inflamma-tion with colchicine dates back centuries, and with NSAIDs and corticosteroids more than 50 years. Medical therapy to control the under-lying hyperuricemia has been an integral part of gout management since the introduction of probenecid in 1951 and allopurinol in 1966 [24].

Yet with this age-old, comprehensive and widely accepted understanding of the manage-ment of gouty arthritis and hyperuricemia, some patients still do not fare well [5]. Furthermore, the incidence and prevalence of gout continue to rise [6].

Indeed, 100,000300,000 of the nearly 5 million [7] patients with gout are believed to

have disease that is refractory to current thera-pies. These patients often have a chronic, symp-tomatic, destructive arthropathy, frequent acute flares of joint pain and disfiguring tophaceous deposits [8]. Patients arrive at this state after widely varying clinical histories. Some patients present with disease in an atypical fashion, elud-ing diagnosis. Others are properly diagnosed but do not respond adequately to traditional UA-lowering therapies, are underdosed, are noncompliant or may be allergic to or intoler-ant of their treatment [9]. As a result of their advanced disease process, these patients have a significantly impaired quality of life (QOL) [8]. Furthermore, significant comorbidities long associated with gout, including cardiovascular disease, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease and obesity, may complicate its management [10].

Fundamental to treating patients with advanced gout is an imperative to mobilize monosodium urate deposits from articular struc-tures and tophaceous deposits, thereby prevent-ing joint destruction and improving function. It has been demonstrated that the more profoundly the serum uric acid (SUA) can be lowered, the more effectively tophaceous deposits can be resolved [11]. Standard therapies often take years to resolve tophi and bring chronic gouty arthrop-athy under control. Indeed, some propose that the treatment target for SUA in patients with gout of this severity should be well below the current standard of 6 mg/dl [12,13]. Profound

Although pharmacologic therapies for hyperuricemia in patients with gout have been well established and are reasonably effective, a small proportion of patients are refractory to treatment and/or present with articular disease so severe as to render standard treatments inadequate. Pegloticase, a PEGylated mammalian urate oxidase with a novel mechanism of action, was recently approved in the USA for the treatment of chronic gout in adult patients refractory to conventional therapy. This paper outlines the development of this unique agent and provides details of the Phase III clinical trial program. A discussion of patient selection, treatment considerations, and risk management for infused pegloticase follows. As a new class of biologic agent offering documented and dramatic effects on lowering serum uric acid and remarkably rapid outcomes in resolving tophi, pegloticase can provide safe and effective management of hyperuricemia and gout for many patients, particularly those who have a high disease burden or who have previously failed to respond to other therapies.

KEYWORDS: biologic therapy n chronic gout n hyperuricemia n pegloticase Herbert SB Baraf* & Alan K MatsumotoGeorge Washington University, Center for Rheumatology & Bone Research, a Division of Arthritis & Rheumatism Associates, 2730 University Blvd West, Wheaton, MD 20902, USA *Author for correspondence: Tel.: +1 301 942 7600 Fax: +1 301 942 3132

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Pegloticase: a new biologic for treating advanced gout Drug Evaluation

144 Int. J. Clin. Rheumatol. (2012) 7(2) future science group

Drug Evaluation Baraf & Matsumoto

lowering of SUA would be expected to resolve the manifestations of gout in a more reasonable time frame in the severely affected patient. Recently developed urate-lowering therapies directed at the enzymatic conversion of urate to allantoin (Figure1) [1416] may accomplish this goal [8].

Current therapies targeting hyperuricemiaIn September 2010, the US FDA approved pegloticase for the treatment of hyperuricemia in patients with gout who fail to normalize SUA on standard oral hypouricemic therapies and whose signs and symptoms of gout are in adequately con-trolled [101]. Until now, conventional therapies to treat hyperuricemia have fallen into two cat-egories: uricosuric agents and xanthine oxidase inhibitors [12].

Uricosuric agents inhibit the renal transporter proteins URAT-1 and GLUT-9, among others, in the proximal tubule, interfering with UA resorp-tion [17]. Probenecid is the only uricosuric drug currently available in the USA. It is not effective in patients with moderate renal insufficiency (cre-atinine clearance

Pegloticase: a new biologic for treating advanced gout Drug EvaluationDrug Evaluation Baraf & Matsumoto 145future science group

therapy and are at reduced risk for hypersensitiv-ity reactions, a carefully monitored escalation of dose above recommended levels based on creati-nine clearance may be an option [22]. In patients with good (or moderately impaired) renal func-tion, the hypouricemic effect of xanthine oxidase inhibitors may be increased by coadministration with uricosuric agents [23].

Pegloticase is the f irst biologic product approved for the treatment of refractory chronic gout in the USA and is the first pegylated thera-peutic agent to lower UA through the enzy-matic conversion of UA to allantoin (Figure1). Its use is restricted to patients with severe mani-festations of chronic gout who are refractory to currently available therapies [24,25]. Such patients have had few treatment options until now. Indeed, even with maximal dosing of oral UA-lowering therapies, the time to improve-ment of the chronic features of gout, particu-larly tophaceous deposits and chronic persistent synovitis, is slow, leaving patients with signifi-cant functional impairments and at risk for further complications.

Pegloticase: novel therapy for refractory chronic goutThe purine degradation pathway in most mam-malian species leads to the generation of UA, which is acted upon by urate oxidase (uricase) to generate allantoin. Humans, some higher pri-mates, and various new world monkey species lack the uricase enzyme and are susceptible to elevated serum concentrations of UA. Given its role in other species, uricase replacement thera-pies have long been considered for the treatment of patients with severe gout. Early attempts, however, to treat this patient population with uricase extracted from different sources failed to achieve sustainable tolerability or efficacy. Rasburicase is a recombinant urate oxidase that is approved as a single dose to treat elevations in plasma uric acid (PUA) in patients at risk of tumor lysis resulting from chemotherapy [26]. Rasburicase was tested in patients with hyper-uricemia and gout but its use was limited by immunogenicity and a short half-life.

Preclinical summaryPegloticase is a recombinant mammalian urate oxidase enzyme produced by a genetically modi-fied strain of Escherichia coli that has been cova-lently conjugated to monomethoxypoly (ethyl-ene glycol). Pegloticase converts UA to the more soluble product, allantoin, which is then easily excreted in the urine. PEGylation increases the

half-life and decreases the immunogenicity of the enzyme [3]. Age, sex, weight and creatinine clearance do not affect the pharmacokinetics of pegloticase, and therefore dose adjustment is not a concern. However, significant covariates revealed in the model for drug clearance and volume of distribution included body surface area and the presence of antipegloticase anti-bodies [25].

Early phase clinical experience: Phase I trial with subcutaneous administrationIn an initial Phase I clinical trial, 13 patients with severe gout, including 11 with tophaceous gout and a mean baseline PUA concentration of >11 mg/dl, were treated with a single subcuta-neous injection of 424 mg of pegloticase. The mean PUA decreased to approximately 3 mg/dl in 11 patients within 7 days. At 21 days postin-jection, the mean PUA remained

Pegloticase: a new biologic for treating advanced gout Drug Evaluation

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Antibodies against pegloticase developed in nine patients, in whom enzyme clearance was rapid, but no allergic reactions occurred. There were no severe or serious adverse events (AEs) in this study; gout flare was the most common AE, reported in 14 patients. In addition, the bioavail-ability, efficacy and tolera