Pegloticase: a New Biologic for Treating Advanced Gout
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Drug Evaluation Pegloticase: a new biologic for treating advanced gout 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 Matsumoto Among the rheumatic diseases, few are as well have disease that is refractory to current thera- George Washington University, understood as gout. The cause of gout, prolonged pies. These patients often have a chronic, symp- Center for Rheumatology & Bone Research, a Division of Arthritis & hyperuricemia resulting from excess production tomatic, destructive arthropathy, frequent acute Rheumatism Associates, 2730 or decreased excretion of uric acid (UA), was first flares of joint pain and disfiguring tophaceous University Blvd West, Wheaton, MD 20902, USA described by Garrod in the mid-19th century [1]. deposits [8]. Patients arrive at this state after *Author for correspondence: Garrod also described a semiquantitative method widely varying clinical histories. Some patients Tel.: +1 301 942 7600 for measuring UA crystals in serum, commonly present with disease in an atypical fashion, elud- Fax: +1 301 942 3132 [email protected] called the ‘thread test’, and wisely postulated that ing diagnosis. Others are properly diagnosed urate deposition was the cause of gouty inflam- but do not respond adequately to traditional mation. The presence of UA in renal stones and UA-lowering therapies, are underdosed, are monosodium urate in tophi was documented noncompliant or may be allergic to or intoler- well before that by Woolaston in 1797 [1]. Even ant of their treatment [9]. As a result of their the genetic basis of our species’ susceptibility to advanced disease process, these patients have hyperuricemia, the lack of a functional uricase a significantly impaired quality of life (QOL) gene, has been understood for decades. [8]. Furthermore, significant comorbidities long The medical management of gout also associated with gout, including cardiovascular has a long history. Hippocrates wrote that he disease, hypertension, hyperlipidemia, diabetes “habitually employed purgatives in the parox- mellitus, chronic kidney disease and obesity, ysms of gout”. The control of joint inflamma- may complicate its management [10]. tion with colchicine dates back centuries, and Fundamental to treating patients with with NSAIDs and corticosteroids more than advanced gout is an imperative to mobilize 50 years. Medical therapy to control the under- monosodium urate deposits from articular struc- lying hyperuricemia has been an integral part tures and tophaceous deposits, thereby prevent- of gout management since the introduction of ing joint destruction and improving function. It probenecid in 1951 and allopurinol in 1966 [2–4]. has been demonstrated that the more profoundly Yet with this age-old, comprehensive and the serum uric acid (SUA) can be lowered, the widely accepted understanding of the manage- more effectively tophaceous deposits can be ment of gouty arthritis and hyperuricemia, some resolved [11]. Standard therapies often take years patients still do not fare well [5]. Furthermore, to resolve tophi and bring chronic gouty arthrop- the incidence and prevalence of gout continue athy under control. Indeed, some propose that to rise [6]. the treatment target for SUA in patients with Indeed, 100,000–300,000 of the nearly gout of this severity should be well below the 5 million [7] patients with gout are believed to current standard of 6 mg/dl [12,13]. Profound part of 10.2217/IJR.11.79 © 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(2), 143–154 ISSN 1758-4272 143 Drug Evaluation Baraf & Matsumoto Pegloticase: a new biologic for treating advanced gout Drug Evaluation lowering of SUA would be expected to resolve the kidneys. Allopurinol, the first xanthine oxidase manifestations of gout in a more reasonable time inhibitor, was introduced in the USA for the frame in the severely affected patient. Recently treatment of gout and hyperuricemia in 1966 developed urate-lowering therapies directed at [19]. It is the most widely prescribed xanthine the enzymatic conversion of urate to allantoin oxidase inhibitor and accounts for 90% of urate- (Figure 1) [14–16] may accomplish this goal [8]. lowering therapy in the USA [18]. Allopurinol (and its primary metabolite, oxypurinol) is Current therapies targeting highly dependent on the kidney for elimina- hyperuricemia tion and requires dose adjustment in patients In September 2010, the US FDA approved with renal impairment [18]. Allopurinol hyper- pegloticase for the treatment of hyperuricemia in sensitivity syndrome, a life-threatening reaction patients with gout who fail to normalize SUA on to treatment, is a well-documented albeit rare standard oral hypouricemic therapies and whose side effect of this therapy [20]. signs and symptoms of gout are in adequately con- Febuxostat, a nonpurine-selective xanthine trolled [101]. Until now, conventional therapies oxidase inhibitor, was approved for the treat- to treat hyperuricemia have fallen into two cat- ment of hyperuricemia and gout in Europe egories: uricosuric agents and xanthine oxidase (2008) at doses of 80 and 120 mg daily and in inhibitors [12]. the USA (2009) at doses of 40 and 80 mg daily Uricosuric agents inhibit the renal transporter [19]. Febuxostat is less dependent than allopuri- proteins URAT-1 and GLUT-9, among others, in nol on renal function for its elimination, as it is the proximal tubule, interfering with UA resorp- primarily catabolized in the liver [12]. Current tion [17]. Probenecid is the only uricosuric drug clinical knowledge concerning the efficacy of currently available in the USA. It is not effective both allopurinol and febuxostat is derived largely in patients with moderate renal insufficiency (cre- from the Phase III febuxostat trials, which com- atinine clearance <60 ml/min). Benzbromarone, pared varying doses of febuxostat to doses rang- a potent uricosuric drug, is available in Europe ing from 100 to 300 mg of allopurinol. These but its use there has been limited owing to studies showed that allopurinol (300 mg daily) hepatotoxicity [18]. Uricosuric agents are contra- effectively lowered SUA to <6 mg/dl in approxi- indicated in patients with a history of renal stones mately 40% of patients at their final visits, com- or who only have one kidney [18]. pared with approximately 40% of patients on Xanthine oxidase inhibitors decrease the UA febuxostat 40 mg daily, and 60–70% of patients concentration by inhibiting the enzyme respon- on 80 or 120 mg [12,19]. sible for the conversion of xanthine to hypo- Several approaches have been described to xanthine and hypoxanthine to UA in the purine optimize urate lowering with existing oral degradation pathway (Figure 1). This results in the agents. In patients with a history of allopurinol generation of higher concentrations of xanthine hypersensitivity syndrome, some have advocated and hypoxanthine, which are more soluble than desensitization using controlled dose escalation UA and are more readily cleared through the [21]. For patients who have tolerated allopurinol Cell breakdown Diet Purines Tophaceous deposits Xanthine Xanthine oxidase oxidase Pegloticase Hypoxanthine Xanthine Uric acid Allantoin ++ uricosuric agents Xanthine oxidase inhibitors Urinary Urinary excretion excretion Figure 1. Therapeutic targets in urate metabolism. 144 Int. J. Clin. Rheumatol. (2012) 7(2) future science group Drug Evaluation Baraf & Matsumoto Pegloticase: a new biologic for treating advanced gout Drug Evaluation therapy and are at reduced risk for hypersensitiv- half-life and decreases the immunogenicity of ity reactions, a carefully monitored escalation of the enzyme [3]. Age, sex, weight and creatinine dose above recommended levels based on creati- clearance do not affect the pharmacokinetics nine clearance may be an option [22]. In patients of pegloticase, and therefore dose adjustment is with good (or moderately impaired) renal func- not a concern. However, significant covariates tion, the hypouricemic effect of xanthine oxidase revealed in the model for drug clearance and inhibitors may be increased by coadministration volume of distribution included body surface with uricosuric agents [23]. area and the presence of antipegloticase anti- Pegloticase is the first biologic product bodies [25]. approved for the treatment of refractory chronic gout in the USA and is the first pegylated thera- Early phase clinical experience: peutic agent to lower UA